Nuclear receptor binding agents

ABSTRACT

The present invention relates to a novel class of selective estrogen receptor modulators (SERMs). The SERM compounds are applicable for use in the prevention and/or treatment of a variety of diseases and conditions including prevention and treatment of cancers such as prostate and breast cancer, osteoporosis, hormone-related diseases, hot flashes or vasomotor symptoms, neurological disorders, cardiovascular disease and obesity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part application of U.S. patentapplication Ser. No. 11/785,251 filed Apr. 16, 2007 now U.S. Pat. No.8,158,828, which is a Continuation-In-Part application of U.S. patentapplication Ser. No. 11/604,884 filed Nov. 28, 2006 now abandoned, whichclaims the benefit of U.S. Provisional Application Ser. No. 60/739,898,filed Nov. 28, 2005, which are all hereby incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to a novel class of nuclear receptorbinding agents (NRBAs). The NRBA compounds are applicable for use in theprevention and/or treatment of a variety of diseases and conditionsincluding, inter alia, prevention and treatment of hormone-relateddiseases, cancers, inflammation, osteoporosis, peripheral vasculardisease, neurological disorders, ocular disorders, cardiovasculardisease and obesity.

BACKGROUND OF THE INVENTION

The nuclear hormone receptor superfamily of ligand activatedtranscription factors is present in various tissues, and responsible fora multitude of effects in these tissues.

The nuclear receptor (NR) superfamily presently comprises approximately48 different proteins, most of which are believed to function as ligandactivated transcription factors, exerting widely different biologicalresponses by regulating gene expression. Members of this family includereceptors for endogenous small, lipophilic molecules, such as steroidhormones, retinoids, vitamin D and thyroid hormone.

The nuclear receptor (NR) superfamily includes the steroid nuclearreceptor subfamily, such as the mineralocorticoid receptor (MR) (oraldosterone receptor), the estrogen receptors (ER), ER alpha and ERbeta, the androgen receptor (AR), the progesterone receptors (PR),glucocorticoid receptors (GR) and others. Also closely related instructure are the estrogen related receptors (ERRs) ERR-alpha, ERR-betaand ERR-gamma. The steroid nuclear receptors perform important functionsin the body some of which are related to the transcriptional homeostasisof electrolyte and water balance, growth, development and wound healing,fertility, stress responses, immunological function, and cognitivefunctioning. The effects may be mediated by cytosolic or nuclear events.The effects may be mediated by cytosolic or nuclear events. Accordingly,compounds that modulate (i.e. antagonize, agonize, partially antagonize,partially agonize) the activity of steroid nuclear receptors areimportant pharmaceutical agents that have specific utility in a numberof methods, as well as for the treatment and prevention of a wide rangeof diseases and disorders modulated by the activity of steroid nuclearreceptors.

Members of the steroid nuclear receptor sub-family exhibit significanthomology to each other and possess closely related DNA and ligandbinding domains.

Given the close similarity in ligand binding domains of the steroidnuclear receptors, it is not surprising that many naturally occurringand synthetic molecules possess the ability to modulate the activity ofmore than one steroid nuclear receptor.

SUMMARY OF THE PRESENT INVENTION

In one embodiment, this invention provides a nuclear receptor bindingagent (NRBA), which in one embodiment is a selective estrogen receptormodulator (SERM) compound or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, ester, hydrate or any combinationthereof, represented by the structure of formula I:

wherein

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

wherein;R₆ and R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂ or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂ or SO₂NHR;j, k, l are independently 1-5;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons; andif X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₂ is OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle when k is 1, then R₁ or R₃ is not hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino;if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₃ is OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle when 1 is one, then R₁ or R₂ is not hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino.

In one embodiment, this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula I:

wherein

-   -   X is CS, branched alkyl, branched alkyl with haloalkyl side        chain, haloalkyl, SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl, OCH₂CH₂NR₄R₅, Z(CH₂)_(q)Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic;

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

wherein R₆ or R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently 1-5;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons orcyclic alkyl of 3-8 carbons.

In one embodiment this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula II:

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR; q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons orcyclic alkyl of 3-8 carbons; andif X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₂ is OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle when k is 1, then R₁ or R₃ is not hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino;if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₃ is OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle when 1 is one, then R₁ or R₂ is not hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino.

In one embodiment this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula II:

wherein

-   -   X is CS, branched alkyl, branched alkyl with haloalkyl side        chain, haloalkyl, SO, or SO₂;        R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde,        COOH, CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano,        nitro, CF₃, NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl,        aryl, protected hydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅,        Z-Alk-heterocycle or OCH₂CH₂-heterocycle in which the        heterocycle is a 3-7 membered substituted or unsubstituted        heterocyclic ring, optionally aromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

wherein R₆ or R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons orcyclic alkyl of 3-8 carbons.

In another embodiment this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula III:

whereinA is a ring selected from

B is a ring selected from

C is a ring selected from

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

W₁ and W₂ are independently, hydrogen, halogen, aldehyde, COOH, CHNOH,CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃, NH₂, NHR,NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protected hydroxyl,OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic;

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;

R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;

Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR; q is 1-5;n is 0-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons;A, B and C cannot simultaneously be a benzene ring; andif X is (CH₂)_(q), CO or C(O)(CH₂)_(q), A is pyridyl ring and B and Care phenyl rings and C is substituted with OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle, then A or B is not substituted with hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino;If X is (CH₂)_(q), CO or C(O)(CH₂)_(q), A is pyridyl ring and B and Care phenyl rings and B is substituted with OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle, then A or C is not substituted with hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino.

In another embodiment, this invention provides, a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula IV:

wherein

-   -   X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with        haloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ and R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ independently are R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently 1-5;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons orcyclic alkyl of 3-8 carbons.

In another embodiment, this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula V:

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl group, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ and R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ independently are R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, CN, NO₂, alkenyl or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR; q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons.

In one embodiment this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula VI:

wherein

-   -   X is CO, CS, (CH₂)₉, branched alkyl, branched alkyl with        haloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂, R₃, R₈, R₉, and R₁₀ are independently hydrogen, halogen,aldehyde, COOH, CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano,nitro, CF₃, NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl,protected hydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅,Z-Alk-heterocycle or OCH₂CH₂-heterocycle in which the heterocycle is a3-7 membered substituted or unsubstituted heterocyclic ring, optionallyaromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, CN, NO₂, alkenyl or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently 1-4;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons; and

-   -   if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₂ is OCH₂CH₂NR₄R₅,        or OCH₂CH₂-heterocycle when k is 1, and R₉ is hydrogen, lower        alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro        or amino, then    -   R₁ or R₃ is not hydrogen, lower alkyl (1-4 carbons), lower        alkoxy (1-4 carbons), halogen, nitro or amino;    -   if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₃ is OCH₂CH₂NR₄R₅,        or OCH₂CH₂-heterocycle when 1 is one, and R₁₀ is hydrogen, lower        alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro        or amino;    -   then R₁ or R₂ is not hydrogen, lower alkyl (1-4 carbons), lower        alkoxy (1-4 carbons), halogen, nitro or amino.

In another embodiment, the 3-7 membered substituted or unsubstitutedheterocyclic ring, optionally aromatic, is represented by the structureof formula B:

wherein Y is CH₂, CH, bond, O, S, NH, N or NR;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;M is 0-4;n is 0-4;wherein m and n cannot both be zero.

In one embodiment B is substituted or unsubstituted piperidine; inanother embodiment B is substituted or unsubstituted pyrrolidine; inanother embodiment B is substituted or unsubstituted morpholine; inanother embodiment B is substituted or unsubstituted piperazine.

In one embodiment this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula VII:

wherein X is CS, (CH₂)_(q), branched alkyl, branched alkyl withhaloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;or X is CO, and OH is meta or ortho.

In another embodiment this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula VIII:

wherein X is CS, (CH₂)_(q), branched alkyl, branched alkyl withhaloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;or X is CO, and OH is meta or ortho.

In another embodiment, this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula IX:

wherein X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl withhaloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, a 3 to 7 membered heteroaryl group, or R₄ and R₅ formtogether with the nitrogen atom a 3-7 heterocyclic ring, optionallyaromatic, is represented by the structure of formula B:

wherein Y is CH₂, CH, bond, O, S, NH, N or NR;if B is aryl then z is 1; and if B is cycloalkyl z is 2;m is 0-4;n is 0-4;wherein m and n cannot both be zero;q is 1-5;p is 1-4;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂ or OH.

In another embodiment, this invention provides a NRBA, which in oneembodiment is a SERM compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula X:

wherein

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂, R₃, R₈, R₉, R₁₀, R₁₁, R₁₂ and R₁₃ are independently hydrogen,halogen, aldehyde, COOH, CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl,alkoxy, cyano, nitro, CF₃, NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R,alkyl, aryl, protected hydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅,Z-Alk-heterocycle or OCH₂CH₂-heterocycle in which the heterocycle is a3-7 membered substituted or unsubstituted heterocyclic ring, optionallyaromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ are independently is R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, CN, NO₂, alkenyl or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group; or R₄ and R₅form together with the nitrogen atom a 3-7 heterocyclic ring, optionallyaromatic, is represented by the structure of formula B:

wherein Y is CH₂, CH, bond, O, S, NH, N or NR;if B is aryl then z is 1; and if B is cycloalkyl z is 2;m is 0-4;n is 0-4;wherein m and n cannot both be zero;q is 1-5;p is 1-4;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂ or OH;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently 1-3;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons; and

-   -   if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₂ is OCH₂CH₂NR₄R₅,        or OCH₂CH₂-heterocycle when k is 1, and R₉ and R₁₂ are hydrogen,        lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen,        nitro or amino, then    -   R₁ or R₃ is not hydrogen, lower alkyl (1-4 carbons), lower        alkoxy (1-4 carbons), halogen, nitro or amino;    -   if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₃ is OCH₂CH₂NR₄R₅,        or OCH₂CH₂-heterocycle when 1 is one, and R₁₀ and R₁₃ are        hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons),        halogen, nitro or amino;    -   then R₁ or R₂ is not hydrogen, lower alkyl (1-4 carbons), lower        alkoxy (1-4 carbons), halogen, nitro or amino

In one embodiment this invention provides a method of reducingcirculating lipid levels in a male subject with prostate cancer havingundergone Androgen Deprivation Therapy (ADT), said method comprisingadministering to said subject a composition comprising a nuclearreceptor binding agent (NRBA) compound or its pharmaceuticallyacceptable salt, hydrate, N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treatingatherosclerosis and its associated diseases including cardiovasculardisorders, cerebrovascular disorders, peripheral vascular disorders, andintestinal vascular disorders in a subject with prostate cancer havingundergone Androgen Deprivation Therapy (ADT), comprising administeringto said subject a composition comprising a nuclear receptor bindingagent (NRBA) compound or its pharmaceutically acceptable salt, hydrate,N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treating ischemiain a tissue of a subject with prostate cancer having undergone AndrogenDeprivation Therapy (ADT), comprising administering to said subject acomposition comprising a nuclear receptor binding agent (NRBA) compoundor its pharmaceutically acceptable salt, hydrate, N-oxide, or anycombination thereof.

In another embodiment this invention provides a method of (i) treatingand preventing osteoporosis; (ii) treating, preventing or reducing therisk of mortality from cardiovascular disease in a subject; (iii)improving a lipid profile; (iv) reducing the incidence of, inhibiting,suppressing, or treating androgen-deprivation induced osteoporosis, bonefractures and/or loss of bone mineral density (BMD) in men havingprostate cancer; (v) ameliorating symptoms and/or clinical complicationsassociated with menopause in a female subject; (vi) treating, preventingor reducing the severity of Alzheimer's disease; (vii) treating,preventing, suppressing, inhibiting, or reducing the incidence of hotflashes, gynecomastia, and/or hair loss in a male; (viii) treating,suppressing, inhibiting or reducing the risk of developing prostatecancer in a subject with prostate cancer; (ix) treating, suppressing,inhibiting or reducing the amount of precancerous precursors of prostateadenocarcinoma lesions; (x) treating, suppressing, inhibiting orreducing the risk of developing breast cancer in a subject; (xi)treating, suppressing, inhibiting or reducing the risk of developingcolon cancer in a subject; (xii) treating, suppressing, inhibiting orreducing the risk of developing leukemia in a subject; (xiii) treating,suppressing, inhibiting or reducing the risk of developing bladdercancer in a subject; (xiv) treating, suppressing, inhibiting or reducingthe incidence of inflammation in a subject; (xv) treating, suppressing,inhibiting or reducing the incidence of neurological disorders in asubject; (xvi) treating, suppressing, inhibiting or reducing theincidence of ocular disorders, (xvii) reducing the lipid profile of amale subject with prostate cancer having undergone ADT, (xviii)treating, suppressing, inhibiting or reducing the risk ofatherosclerosis of a male subject with prostate cancer having undergoneADT. (xix) treating, suppressing, inhibiting or reducing the risk ofischemia of a male subject with prostate cancer having undergone ADTusing the nuclear receptor binding agents (NRBAs) of the invention,which in one embodiment are SERM compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1: Effects of the indicated compounds on ER-α transactivation. COSor 293 cells plated in DME without phenol red+10% charcoal strippedfetal bovine serum (csFBS) at 90,000 cells per well of 24 well plateswere transfected with 0.25 μg ERE-LUC, 0.02 μg CMV-LUC (Renilla) and 25ng of ER-α by lipofectamine. Twenty four hours after transfection, thecells were treated as indicated in the figure, harvested 48 hrs aftertransfection and were assayed for firefly and renilla luciferase.

FIG. 2: Effect of the indicated compounds on ER-β transactivation. COSor 293 cells plated in DME without phenol red+10% csFBS at 90,000 cellsper well of a 24 well plate were transfected with 0.25 μg ERE-LUC, 0.02μg CMV-LUC (Renilla) and 50 ng of ER-β by lipofectamine. Twenty fourhours after transfection, the cells were treated as indicated in thefigure, harvested 48 hrs after transfection and were assayed for fireflyand renilla luciferase.

FIG. 3: Effect of the indicated compounds on AR transactivation. COScells plated in DME without phenol red+10% csFBS at 90,000 cells perwell of a 24 well plate were transfected with 0.25 μg ARE-LUC, 0.02 μgCMV-LUC (Renilla) and 12.5 ng of AR by lipofectamine. Twenty four hoursafter transfection, the cells were treated as indicated in the figure,harvested 48 hrs after transfection and were assayed for firefly andrenilla luciferase.

FIG. 4: Compound 4a functions as a partial agonist of ER action in MCF-7cells. MCF-7 cells were plated at 500,000 cells per well of a 6 wellplate. The cells were serum starved for 3 days and then were treated ornot treated as indicated in the figure for 16 hrs. RNA was isolated andthe message levels of pS2 (gene encoding the trefoil peptides) measuredand normalized to 18S ribosomal RNA by realtime polymerase chainreaction (rtPCR).

FIG. 5: Effect of the indicated compounds on ER-α transactivation. COSor 293 cells plated in DME without phenol red+10% csFBS at 90,000 cellsper well of a 24 well plate were transfected with 0.25 μg ERE-LUC, 0.02μg CMV-LUC (Renilla) and 5 ng of ER-α by lipofectamine. Twenty fourhours after transfection, the cells were treated as indicated in thefigure, harvested 48 hrs after transfection and were assayed for fireflyand renilla luciferase.

FIG. 6: Effect of the indicated compounds on ER-β transactivation. COSor 293 cells plated in DME without phenol red+10% csFBS at 90,000 cellsper well of a 24 well plate were transfected with 0.25 μg ERE-LUC, 0.02μg CMV-LUC (Renilla) and 50 ng of ER-β by lipofectamine. Twenty fourhours after transfection, the cells were treated as indicated in thefigure, harvested 48 hrs after transfection and assayed for firefly andrenilla luciferase.

FIG. 7: Effect of the indicated compounds on TRAP positivemultinucleated osteoclasts. Bone marrow cells from rat femur wascultured in Alpha MEM+10% csFBS without phenol red in the presence orabsence of 30 ng/ml RANKL and 10 ng/ml GMCSF. The cells were treated for12 days and were stained for tartarate resistant acid phosphataseactivity (TRAP) and multinucleated osteoclasts were counted.

FIG. 8: Some embodiments of this invention include inhibition ofandrogen independent prostate cancer cell growth via the compounds ofthis invention. PC-3 cells were plated in RPMI+10% csFBS at 6000 cellsper well of a 96 well plate. Medium was changed to RPMI+1% csFBS withoutphenol red and then treated for 72 hrs with increasing concentrations ofSERMs.

FIG. 9: Effect of the indicated compounds on ER-α transactivation. COSor 293 cells plated in DME without phenol red+10% csFBS per well of a 24well plate were transfected with 0.25 μg ERE-LUC, 0.02 μg CMV-LUC(Renilla) and 25 ng of ER-α by lipofectamine. Twenty four hours aftertransfection, the cells were treated as indicated in the figure,harvested 48 hrs after transfection and were assayed for firefly andrenilla luciferase.

FIG. 10: Effect of the indicated compounds on ER-β transactivation. COSor 293 cells plated in DME+10% csFBS at 90,000 cells per well of a 24well plate were transfected with 0.25 μg ERE-LUC, 0.02 μg CMV-LUC(Renilla) and 50 ng of ER-β by lipofectamine. Twenty four hours aftertransfection, the cells were treated as indicated in the figure,harvested 48 hrs after transfection and were assayed for firefly andrenilla luciferase.

FIG. 11: Agonistic activity of the indicated compounds in MCF-7 cells.MCF-7 cells were plated at 500,000 cells per well of a 6 well plate. Thecells were starved for 3 days and then were treated or not treated asindicated in the figure for 16 hrs. RNA was isolated and the messagelevels of pS2 gene measured and normalized to 18S ribosomal RNA byrealtime rtPCR.

FIG. 12: Estrogenic activity of compound 3d, as compared to toremifene(Tor) and estradiol (E2), as measured by in vivo increased uterinetissue weight (mg).

FIG. 13: Estrogenic activity of compounds 4a and 4h, as compared totoremifene (Tor) and estradiol (E2), as measured by in vivo increaseduterine tissue weight (mg).

FIG. 14: Effects of the indicated compounds on TRAP positivemultinucleated osteoclasts.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention provides, in some embodiments, novel NRBAs, whichin some embodiments are SERM compounds, and compositions comprising thesame.

This invention provides, in some embodiments, NRBAs, which in oneembodiment are SERMs. In one embodiment, the phrase “Selective EstrogenReceptor Modulator” or “SERM” refers to a compound that affects estrogenreceptor activity. In one embodiment, a SERM exhibits activity as anagonist, or, in another embodiment, as an antagonist, or in anotherembodiment, as a partial agonist, or in another embodiment, as a partialantagonist of the estrogen receptor. In one embodiment, the SERM exertsits effects on the estrogen receptor (e.g., ERα, ERβ or ERRs) in atissue-dependent manner. In some embodiments, the SERMs of thisinvention can act as estrogen receptor agonists in some tissues (e.g.,bone, brain, and/or heart) and as antagonists in other tissue types, forexample in the breast and/or uterine lining.

In one embodiment, a SERM of this invention will have an IC₅₀ or EC₅₀with respect to ERα and/or ERβ of up to about 10 μM as determined usingthe ERα and/or ERβ transactivation assays, as known in the art, or, inother embodiments, as described herein (Example 1, 2). In someembodiments, the SERMs exhibit IC₅₀ or EC₅₀ values (as agonists orantagonists) of not more than about 5 μM. Representative compounds ofthe present invention have been discovered to exhibit agonist orantagonist activity with respect to the estrogen receptor. Compounds ofthe present invention exhibit, in some embodiments, an antagonist oragonist IC₅₀ or EC₅₀ with respect to ERα and/or ERβ of no more thanabout 5 μM, or in some embodiments, no more than about 500 nM, or inother embodiments, not more than about 1 nM, as measured in ERα and/orERβ transactivation assays. The term “IC₅₀” refers, in some embodiments,to a concentration of the SERM which reduces the activity of a target(e.g., ERα or ERβ) to half-maximal level. The term “EC₅₀” refers, insome embodiments, to a concentration of the SERM that produces ahalf-maximal effect

In some embodiments of this invention, the compounds of this inventionare characterized by a structure comprising a phenyl group added tobisphenolic agonists, thus forming triphenyl agents. In someembodiments, the triphenyl groups are rigidly held by an amide bond. Inaddition to the triphenyl moiety, in some embodiments, the SERMs may becharacterized by a structure comprising a basic side chain (tertiaryamine), which in some embodiments, is present as an N-substitutedethanolamine sidechain appended to one or two of the phenolic ethergroups.

SERMs:

In one embodiment, the present invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula I:

wherein

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, (C)O(CH₂)_(q), SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently 1-5;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons; andif X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₂ is OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle when k is 1, then R₁ or R₃ is not hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino;

if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₃ is OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle when 1 is one, then R₁ or R₂ is not hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino.

In another embodiment, this invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula I:

wherein

-   -   X is CS, branched alkyl, branched alkyl with haloalkyl side        chain, haloalkyl, SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl, OCH₂CH₂NR₄R₅, Z(CH₂)_(q)Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

wherein R₆ or R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently 1-5;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons.

In another embodiment this invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula II:

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons; andif X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₂ is OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle when k is 1, then R₁ or R₃ is not hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino;if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₃ is OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle when 1 is one, then R₁ or R₂ is not hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino.

In another embodiment, according to this aspect of the invention, X isCO and R₁, R₂ and R₃ are OH, or in another embodiment X is CO and R₁ isOCH₂CH₂-piperidine HCl salt, R₂ is H and R₃ is OH.

In another embodiment this invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula II:

wherein

-   -   X is CS, branched alkyl, branched alkyl with haloalkyl side        chain, haloalkyl, SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, aldehyde, COOH,CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

wherein R₆ and R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons.

In another embodiment the present invention provides, a SERM compound orits prodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula III:

whereinA is a ring selected from

B is a ring selected from

C is a ring selected from

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

W₁ and W₂ are independently, hydrogen, halogen, hydroxyl, aldehyde,COOH, CHNOH, CH═CHCO₂H, hydroxyalkyl, alkoxy, cyano, nitro, CF₃, NH₂,NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protected hydroxyl,OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic;

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;

R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;

Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;q is 1-5;n is 0-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons;and A, B and C cannot simultaneously be a benzene ring; andif X is (CH₂)_(q), CO or C(O)(CH₂)_(q), A is pyridyl ring and B and Care phenyl rings and C is substituted with OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle, then A or B is not substituted with hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino;If X is (CH₂)_(q), CO or C(O)(CH₂)_(q), A is pyridyl ring and B and Care phenyl rings and B is substituted with OCH₂CH₂NR₄R₅, orOCH₂CH₂-heterocycle, then A or C is not substituted with hydrogen, loweralkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro oramino.

In another embodiment this invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula IV:

wherein

-   -   X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with        haloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, halogen, hydroxyl, aldehyde,COOH, CHNOH, CH═CHCO₂H, hydroxyalkyl, alkoxy, cyano, nitro, CF₃, NH₂,NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protected hydroxyl,OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ and R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂, or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently is 1-5;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons.

In another embodiment, this invention provides, a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula V:

X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with haloalkylside chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂ and R₃ are independently, hydrogen, aldehyde, COOH, CHNOH,CH═CHCO₂H, hydroxyalkyl, halogen, hydroxyl, alkoxy, cyano, nitro, CF₃,NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl, protectedhydroxyl group, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅, Z-Alk-heterocycle orOCH₂CH₂-heterocycle in which the heterocycle is a 3-7 memberedsubstituted or unsubstituted heterocyclic ring, optionally aromatic,

or R₁, R₂ and R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ or R₇ are independently R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, CN, NO₂, alkenyl or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons.

In another embodiment, this invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula VI:

wherein

-   -   X is CO, CS, (CH₂)₉, branched alkyl, branched alkyl with        haloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂, R₃, R₈, R₉, and R₁₀ are independently hydrogen, halogen,aldehyde, COOH, CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl, alkoxy, cyano,nitro, CF₃, NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R, alkyl, aryl,protected hydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅,Z-Alk-heterocycle or OCH₂CH₂-heterocycle in which the heterocycle is a3-7 membered substituted or unsubstituted heterocyclic ring, optionallyaromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ are independently is R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, CN, NO₂, alkenyl or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group;Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently 1-4;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons; and

-   -   if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₂ is OCH₂CH₂NR₄R₅,        or OCH₂CH₂-heterocycle when k is 1, and R₉ is hydrogen, lower        alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro        or amino, then    -   R₁ or R₃ is not hydrogen, lower alkyl (1-4 carbons), lower        alkoxy (1-4 carbons), halogen, nitro or amino;    -   if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₃ is OCH₂CH₂NR₄R₅,        or OCH₂CH₂-heterocycle when 1 is 1, and R₁₀ is hydrogen, lower        alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro        or amino;    -   then R₁ or R₂ is not hydrogen, lower alkyl (1-4 carbons), lower        alkoxy (1-4 carbons), halogen, nitro or amino.

In one embodiment of this invention, the 3-7 membered substituted orunsubstituted heterocyclic ring, optionally aromatic, is represented bythe structure of formula B:

wherein Y is CH₂, CH, bond, O, S, NH, N or NR;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, CN, NO₂, alkenyl or OH;if B is aryl then z is 1; and if B is cycloalkyl z is 2;m is 0-4;n is 0-4;wherein m and n cannot both be zero.

In one embodiment B is substituted or unsubstituted piperidine; inanother embodiment B is substituted or unsubstituted pyrrolidine; inanother embodiment B is substituted or unsubstituted morpholine; inanother embodiment B is substituted or unsubstituted piperazine.

In one embodiment this invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula VII:

wherein X is CS, (CH₂)_(q), branched alkyl, branched alkyl withhaloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;or X is CO, and OH is meta or ortho.

In another embodiment this invention provides a selective estrogenreceptor modulator (SERM) compound or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, represented by the structure of formula VIII:

wherein X is CS, (CH₂)_(q), branched alkyl, branched alkyl withhaloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;or X is CO, and OH is meta or ortho.

In another embodiment, this invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula IX:

wherein X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl withhaloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, a 3 to 7 membered heteroaryl group, or R₄ and R₅ formtogether with the nitrogen atom a 3-7 heterocyclic ring, optionallyaromatic, is represented by the structure of formula B:

wherein Y is CH₂, CH, bond, O, S, NH, N or NR;if B is aryl then z is 1; and if B is cycloalkyl z is 2;m is 0-4;is 0-4;wherein m and n cannot both be zero;q is 1-5;p is 1-4;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂ or OH.

In one embodiment B is substituted or unsubstituted piperidine; inanother embodiment B is substituted or unsubstituted pyrrolidine; inanother embodiment B is substituted or unsubstituted morpholine; inanother embodiment B is substituted or unsubstituted piperazine.

In another embodiment, this invention provides a SERM compound or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, represented by thestructure of formula X:

wherein

-   -   X is CO, CS, (CH₂)_(q), branched alkyl, branched alkyl with        haloalkyl side chain, haloalkyl, C(O)(CH₂)_(q), SO, or SO₂;

R₁, R₂, R₃, R₈, R₉, R₁₀, R₁₁, R₁₂ and R₁₃ are independently hydrogen,halogen, aldehyde, COOH, CHNOH, CH═CHCO₂H, hydroxyalkyl, hydroxyl,alkoxy, cyano, nitro, CF₃, NH₂, NHR, NHCOR, N(R)₂, sulfonamide, SO₂R,alkyl, aryl, protected hydroxyl, OCH₂CH₂NR₄R₅, Z-Alk-Q, Z-Alk-NR₄R₅,Z-Alk-heterocycle or OCH₂CH₂-heterocycle in which the heterocycle is a3-7 membered substituted or unsubstituted heterocyclic ring, optionallyaromatic,

or R₁, R₂ or R₃ together with the benzene ring to which the R-group isattached comprises a fused ring system represented by structure A

whereinR₆ and R₇ are independently is R₁, R₂ or R₃;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, CN, NO₂, alkenyl or OH;R₄ and R₅ are independently hydrogen, phenyl, an alkyl group of 1 to 6carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 memberedheterocycloalkyl, or a 3 to 7 membered heteroaryl group; or R₄ and R₅form together with the nitrogen atom a 3-7 heterocyclic ring, optionallyaromatic, is represented by the structure of formula B:

wherein Y is CH₂, CH, bond, O, S, NH, N or NR;if B is aryl then z is 1; and if B is cycloalkyl z is 2;m is 0-4;n is 0-4;wherein m and n cannot both be zero;q is 1-5;p is 1-4;R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl, CN, NO₂ or OH.Z is O, NH, CH₂, or

Q is SO₃H, CO₂H, CO₂R, NO₂, tetrazole, SO₂NH₂, or SO₂NHR;j, k, l are independently 1-3;q is 1-5;Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, orcyclic alkyl of 3-8 carbons; and

-   -   if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₂ is OCH₂CH₂NR₄R₅,        or OCH₂CH₂-heterocycle when k is 1, and R₉ and R₁₂ are hydrogen,        lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen,        nitro or amino, then    -   R₁ or R₃ is not hydrogen, lower alkyl (1-4 carbons), lower        alkoxy (1-4 carbons), halogen, nitro or amino;    -   if X is (CH₂)_(q), CO or C(O)(CH₂)_(q), and R₃ is OCH₂CH₂NR₄R₅,        or OCH₂CH₂-heterocycle when 1 is one, and R₁₀ and R₁₃ are        hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons),        halogen, nitro or amino;    -   then R₁ or R₂ is not hydrogen, lower alkyl (1-4 carbons), lower        alkoxy (1-4 carbons), halogen, nitro or amino.

In one embodiment the NRBA or SERM compound of this invention is4-methoxy-N,N-bis-(4-methoxyphenyl)-benzamide (2a). In one embodimentthe NRBA or SERM compound of this invention is3-methoxy-N,N-bis-(4-methoxyphenyl)-benzamide (2b). In one embodimentthe NRBA or SERM compound of this invention is4-methoxy-N-(4-methoxyphenyl)-N-(3-methoxyphenyl)-benzamide (2c). In oneembodiment the NRBA or SERM compound of this invention isN,N-bis-(4-methoxyphenyl)-benzamide (2d). In one embodiment the NRBA orSERM compound of this invention is 4-Methoxy-N,N-diphenyl-benzamide(2e). In one embodiment the NRBA or SERM compound of this invention is3-methoxy-N,N-diphenyl-benzamide (2f). In one embodiment the NRBA orSERM compound of this invention is N,N-diphenyl-benzamide (2g). In oneembodiment the NRBA or SERM compound of this invention isN-(4-methoxyphenyl)-N-phenyl-benzamide (2h). In one embodiment the NRBAor SERM compound of this invention isN-(3-methoxyphenyl)-N-phenyl-benzamide (2i). In one embodiment the NRBAor SERM compound of this invention is4-methoxy-N-(4-methoxyphenyl)-N-phenyl-benzamide (2j). In one embodimentthe NRBA or SERM compound of this invention is4-methoxy-N-(3-methoxyphenyl)-N-phenyl-benzamide (2k). In one embodimentthe NRBA or SERM compound of this invention isN,N-bis(4-methoxyphenyl)-4-fluorobenzamide (2l). In one embodiment theNRBA or SERM compound of this invention is4-methoxy-N,N-diphenyl-sulfonamide (2m). In one embodiment the NRBA orSERM compound of this invention is4-methoxy-N-(4-methoxyphenyl)-N-(4-fluorophenyl)-benzamide (2n). In oneembodiment the NRBA or SERM compound of this invention is4-methoxy-N-(4-methoxyphenyl)-N-(1-naphthyl)-benzamide (2o). In oneembodiment the NRBA or SERM compound of this invention isN-(4-methoxyphenyl)-N-(4-benzyloxyphenyl)-1-naphthylamide (2p). In oneembodiment the NRBA or SERM compound of this invention is4-chloro-N-(4-methoxyphenyl)-N-(4-benzyloxyphenyl)-benzamide (2q). Inone embodiment the NRBA or SERM compound of this invention is4-cyano-N-(4-methoxyphenyl)-N-(4-benzyloxyphenyl)-benzamide (2r). In oneembodiment the NRBA or SERM compound of this invention isN-(4-methoxyphenyl)-N-(4-benzyloxyphenyl)-2-naphthylamide (2s). In oneembodiment the NRBA or SERM compound of this invention is4-(benzyloxy)-N-[4-(benzyloxy)phenyl]-N-(4-methoxyphenyl)benzamide (2t).In one embodiment the NRBA or SERM compound of this invention isN-[4-(benzyloxy)phenyl]-4-methoxy-N-(4-methoxyphenyl)benzamide (2u). Inone embodiment the NRBA or SERM compound of this invention isN-[4-(benzyloxy)phenyl]-N-biphenyl-4-yl-4-methoxybenzamide (2v). In oneembodiment the NRBA or SERM compound of this invention is4-cyano-N-(4-methoxyphenyl)-N-phenylbenzamide (2w). In one embodimentthe NRBA or SERM compound of this invention is3-methoxy-N-(4-methoxyphenyl)-N-phenylbenzamide (2x). In one embodimentthe NRBA or SERM compound of this invention is4-cyano-N-(3-methoxyphenyl)-N-phenylbenzamide (2y). In one embodimentthe NRBA or SERM compound of this invention is4-cyano-N,N-diphenylbenzamide (2z). In another embodiment the NRBA orSERM compound of this invention is4-hydroxy-N,N-bis-(4-hydroxyphenyl)-benzamide (3a). In one embodimentthe NRBA or SERM compound of this invention is3-hydroxy-N-bis-(4-hydroxyphenyl)-benzamide (3b). In one embodiment theNRBA or SERM compound of this invention is4-hydroxy-N-(4-hydroxyphenyl)-N-(3-hydroxyphenyl)-benzamide (3c). In oneembodiment the NRBA or SERM compound of this invention isN,N-bis-(4-hydroxyphenyl)-benzamide (3d). In another embodiment the NRBAor SERM compound of this invention is 4-hydroxy-N,N-diphenyl-benzamide(3e). In another embodiment the NRBA or SERM compound of this inventionis 3-hydroxy-N,N-diphenyl-benzamide (3f). In another embodiment the NRBAor SERM compound of this invention isN-(4-hydroxyphenyl)-N-phenyl-benzamide (3g). In another embodiment theNRBA or SERM compound of this invention isN-(3-hydroxyphenyl)-N-phenyl-benzamide (3h). In another embodiment theNRBA or SERM compound of this invention is4-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-benzamide (3i). In one embodimentthe NRBA or SERM compound of this invention is4-hydroxy-N-(3-hydroxyphenyl)-N-phenyl-benzamide (3j). In one embodimentthe NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)-4-fluoro-benzamide (3k). In one embodiment theNRBA or SERM compound of this invention is4-hydroxy-N,N-diphenyl-phenyl-sulfonamide (3l). In another embodimentthe NRBA or SERM compound of this invention is4-hydroxy-N-(4-hydroxyphenyl)-N-(4-fluorophenyl)-benzamide (3m). Inanother embodiment the NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)-1-naphthylamide (3n). In one embodiment theNRBA or SERM compound of this invention is4-hydroxy-N-(1-naphthyl)-N-(4-hydroxyphenyl)-benzamide (3o). In oneembodiment the NRBA or SERM compound of this invention is4-cyano-N,N-bis(4-hydroxyphenyl)-benzamide (3p). In one embodiment theNRBA or SERM compound of this invention is3-Cyano-N,N-bis(4-hydroxyphenyl)-benzamide (3q). In another embodimentthe NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)-2-naphthylamide (3r). In one embodiment theNRBA or SERM compound of this invention is4-cyano-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-hydroxyphenyl)-benzamide(3s). In another embodiment the NRBA or SERM compound of this inventionis3-chloro-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-hydroxyphenyl)-benzamide(3t). In one embodiment the NRBA or SERM compound of this invention isN-biphenyl-4-yl-N-(4-hydroxyphenyl)-4-methoxybenzamide (3u). In oneembodiment the NRBA or SERM compound of this invention isN-biphenyl-4-yl-4-hydroxy-N-(4-hydroxyphenyl)-benzamide (3v). In oneembodiment the NRBA or SERM compound of this invention is4-hydroxy-N-(4-hydroxyphenyl)-N-[4-(2-piperidin-1-ylethoxy)phenyl]-benzamide(3w). In another embodiment the NRBA or SERM compound of this inventionis 3-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-benzamide (3x). In oneembodiment the NRBA or SERM compound of this invention isN-biphenyl-4-yl-4-hydroxy-N-[4-(2-piperidin-1-ylethoxy)phenyl]-benzamide(3y). In another embodiment the NRBA or SERM compound of this inventionis N-(4-hydroxyphenyl)-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-benzamide(4a). In another embodiment the NRBA or SERM compound of this inventionis N-(phenyl)-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-benzamide (4b). Inanother embodiment the NRBA or SERM compound of this invention isN,N-diphenyl-[3-(2-piperidinylethoxy)]-benzamide hydrochloride (4c). Inanother embodiment the NRBA or SERM compound of this invention isN,N-diphenyl-[3-(2-piperidinylethoxy)]-benzamide hydrochloride (4d). Inanother embodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-N-phenyl-[4-(2-piperidin-1-ylethoxy)]-benzamidehydrochloride (4e). In one embodiment the NRBA or SERM compound of thisinvention isN,N-diphenyl-bis[4-(2-piperidin-1-ylethoxy)-phenyl]-sulfonamidehydrochloride (4f). In another embodiment the NRBA or SERM compound ofthis invention isN-(4-fluorophenyl)-N-[4-hydroxyphenyl]-[4-(2-piperidin-1-ylethoxy)]-benzamide(4g). In another embodiment the NRBA or SERM compound of this inventionisN-(4-hydroxyphenyl)-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-4-fluororo-benzamidehydrochloride (4h). In one embodiment the NRBA or SERM compound of thisinvention is3-(2-piperidin-1-ylethoxy)-N,N-bis(4-hydroxyphenyl)-benzamide (4i). Inanother embodiment the NRBA or SERM compound of this invention is4-cyano-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-methoxyphenyl)-benzamide (4j). In another embodiment the NRBA or SERM compound of thisinvention is4-chloro-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-methoxyphenyl)-benzamide(4k) In one embodiment the NRBA or SERM compound of this invention is4-cyano-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-methoxyphenyl)-benzamide(4l). In another embodiment the NRBA or SERM compound of this inventionis3-chloro-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-methoxyphenyl)-benzamide(4m). In another embodiment the NRBA or SERM compound of this inventionis4-methoxy-N-(4-methoxyphenyl)-N-[4-(2-piperidin-1-ylethoxy)phenyl]-benzamide(4n). In one embodiment the NRBA or SERM compound of this invention isN-biphenyl-4-yl-N-(4-hydroxyphenyl)-4-(2-piperidin-1-ylethoxy)-benzamide(4o). In another embodiment the NRBA or SERM compound of this inventionis 4-methoxy-N-phenyl-N-[4-(2-piperidin-1-ylethoxy)phenyl]-benzamide(4p). In another embodiment the NRBA or SERM compound of this inventionis N-(4-hydroxyphenyl)-N-phenyl-3-(2-piperidin-1-ylethoxy)-benzamide(4q). In another embodiment the NRBA or SERM compound of this inventionisN-(4-fluorophenyl)-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-[4-(2-piperidin-1-yl-ethoxy)]-benzamidedihydrochloride (4r). In another embodiment the NRBA or SERM compound ofthis invention isN,N-bis[4-(2-piperidin-1-ylethoxy)-phenyl]-4-fluoro-benzamidedihydrochloride (4s). In another embodiment the NRBA or SERM compound ofthis invention is N,N-bis[4-(2-piperidin-1-ylethoxy)-phenyl]-benzamidedihydrochloride (4t). In one embodiment the NRBA or SERM compound ofthis invention isN-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-phenyl-[4-(2-piperidin-1-ylethoxy)]-benzamidedihydrochloride (4u). In one embodiment the NRBA or SERM compound ofthis invention is4-chloro-N-[4-hydroxyphenyl]-N-(4-methoxyphenyl)-benzamide (5a). In oneembodiment the NRBA or SERM compound of this invention is4-cyano-N-[4-hydroxyphenyl]-N-(4-methoxyphenyl)-benzamide (5b). In oneembodiment the NRBA or SERM compound of this invention is3-chloro-N-[4-hydroxyphenyl]-N-(4-methoxyphenyl)-benzamide (5c). In oneembodiment the NRBA or SERM compound of this invention is4-hydroxy-N-(4-hydroxyphenyl)-N-(4-methoxyphenyl)-benzamide (5d). In oneembodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-4-methoxy-N-(4-methoxyphenyl)-benzamide (5e). In oneembodiment the NRBA or SERM compound of this invention is2-(N-(4-methoxyphenyl)-4-methylphenylsulfonamido)ethyl4-methylbenzenesulfonate (6a). In one embodiment the NRBA or SERMcompound of this invention is(R)-3-bromo-2-hydroxy-N-(4-methoxyphenyl)-2-methylpropanamide (6b). Inone embodiment the NRBA or SERM compound of this invention is(S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide (6c). In oneembodiment the NRBA or SERM compound of this invention is(S)-2-hydroxy-3-(4-methoxyphenoxy)-N-(4-methoxyphenyl)-2-methylpropanamide(6d). In one embodiment the NRBA or SERM compound of this invention is(R)-3-bromo-2-hydroxy-N-(4-hydroxyphenyl)-2-methylpropanamide (6e). Inone embodiment the NRBA or SERM compound of this invention is(S)-2-hydroxy-3-(4-hydroxyphenoxy)-N-(4-hydroxyphenyl)-2-methylpropanamide(6f). In one embodiment the NRBA or SERM compound of this invention is(S)-2-hydroxy-N,3-bis(4-hydroxyphenyl)-2-methylpropanamide (6g). Inanother embodiment the NRBA or SERM compound of this invention is5-[4-methoxy-phenyl]-5H-phenanthridin-6-one (7a). In another embodimentthe NRBA or SERM compound of this invention is5-[4-hydroxy-phenyl]-5H-phenanthridin-6-one (7b). In one embodiment theNRBA or SERM compound of this invention is5-[4-(2-piperidin-1-ylethoxy)-phenyl]-5H-phenanthridin-6-one (7c). Inanother embodiment the NRBA or SERM compound of this invention iscyclohexane-carboxylic acid bis(4-hydroxyphenyl)-amide (8b). In anotherembodiment the NRBA or SERM compound of this invention is4-cyano-N-(4-hydroxyphenyl)-N-phenylbenzamide (10a). In anotherembodiment the NRBA or SERM compound of this invention isN-(biphenyl-4-yl)-4-cyano-N-(4-methoxyphenyl)-benzamide (10b). Inanother embodiment the NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)biphenyl-4-carboxamide (10c). In anotherembodiment the NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)-3,4-dimethylbenzamide (10d). In anotherembodiment the NRBA or SERM compound of this invention isN-(biphenyl-4-yl)-4-cyano-N-(4-hydroxyphenyl)-benzamide (10e). Inanother embodiment the NRBA or SERM compound of this invention is3-fluoro-4-hydroxy-N-(4-hydroxyphenyl)-N-phenylbenzamide (10f). Inanother embodiment the NRBA or SERM compound of this invention is4-fluoro-3-hydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (10 g). In anotherembodiment the NRBA or SERM compound of this invention is4-hydroxy-N,N-bis(4-hydroxyphenyl)-3,5-dimethylbenzamide (10i). Inanother embodiment the NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)-2,3-dimethylbenzamide (10j). In anotherembodiment the NRBA or SERM compound of this invention is3-fluoro-4-hydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (10k). In anotherembodiment the NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)-4-propylbenzamide (10l). In another embodimentthe NRBA or SERM compound of this invention is3,4-dihydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (10m). In anotherembodiment the NRBA or SERM compound of this invention is4-hydroxy-N,N-bis(4-hydroxyphenyl)-3-methylbenzamide (10n). In anotherembodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-4-propylbenzamide(10o). In another embodiment the NRBA or SERM compound of this inventionisN-(4-hydroxyphenyl)-2,3-dimethyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-benzamide(10p). In another embodiment the NRBA or SERM compound of this inventionis N,N-bis(4-hydroxyphenyl)-2,4-dimethylbenzamide (10q). In anotherembodiment the NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)-3,5-dimethylbenzamide (10r). In anotherembodiment the NRBA or SERM compound of this invention isN,N-bis(4-hydroxyphenyl)-4-methylbenzamide (10s). In another embodimentthe NRBA or SERM compound of this invention is4,4′-(2,3-dimethyl-benzylazanediyl)diphenol (10t). In another embodimentthe NRBA or SERM compound of this invention is4-formyl-N,N-bis(4-hydroxyphenyl)-benzamide (10u). In another embodimentthe NRBA or SERM compound of this invention is4-hydroxy-N-(4-hydroxyphenyl)benzamide (10v). In another embodiment theNRBA or SERM compound of this invention isN-cyclohexyl-4-hydroxy-N-(4-hydroxyphenyl)benzamide (10w). In anotherembodiment the NRBA or SERM compound of this invention is4-((4-fluorophenyl)(4-hydroxybenzyl)amino)phenol (10x). In anotherembodiment the NRBA or SERM compound of this invention isN-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(4-hydroxy-phenyl)-benzamide(10y). In another embodiment the NRBA or SERM compound of this inventionis3-Cyano-N-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-benzamide(10z). In another embodiment the NRBA or SERM compound of this inventionis N-(4-hydroxyphenyl)-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)benzamide(11a). In another embodiment the NRBA or SERM compound of this inventionis N,N-bis(4-hydroxyphenyl)-4-(trifluoromethyl)-benzamide (11b). Inanother embodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-4-(trifluoromethyl)-benzamide(11c). In another embodiment the NRBA or SERM compound of this inventionis N,N-bis(4-hydroxyphenyl)-4-nitro-benzamide (11d). In anotherembodiment the NRBA or SERM compound of this invention is3-fluoro-N,N-bis(4-hydroxyphenyl)-benzamide (11e). In another embodimentthe NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1-naphthamide(11f). In another embodiment the NRBA or SERM compound of this inventionis3-fluoro-N-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11g). In another embodiment the NRBA or SERM compound of this inventionisN-(4-hydroxyphenyl)-4-nitro-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11h). In another embodiment the NRBA or SERM compound of this inventionis N,N-bis(4-hydroxyphenyl)-4-methoxy-1-naphthamide (11i). In anotherembodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2-naphthamide(11j). In another embodiment the NRBA or SERM compound of this inventionis 2-hydroxy-N,N,2-tris(4-hydroxyphenyl)-propanamide (11k). In anotherembodiment the NRBA or SERM compound of this invention is4-((hydroxyimino)methyl)-N, N-bis(4-hydroxyphenyl)benzamide (11l). Inanother embodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-2,4-dimethyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11m). In another embodiment the NRBA or SERM compound of this inventionisN-(4-hydroxyphenyl)-3,5-dimethyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11n). In another embodiment the NRBA or SERM compound of this inventionis4-((2,3-dimethylbenzyl)(4-(2-(piperidin-1-yl)ethoxy)phenyl)amino)phenol(11o). In another embodiment the NRBA or SERM compound of this inventionis N,N-bis(4-hydroxyphenyl)-4-pentylbenzamide (11p). In anotherembodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-4-pentyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11q). In another embodiment the NRBA or SERM compound of this inventionis 4-tert-butyl-N,N-bis(4-hydroxyphenyl)benzamide (11r). In anotherembodiment the NRBA or SERM compound of this invention is4-tert-butyl-N-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11s). In another embodiment the NRBA or SERM compound of this inventionis 3-{4-[bis-(4-hydroxy-phenyl)-carbamoyl]-phenyl}-acrylic acid (11t).In another embodiment the NRBA or SERM compound of this invention is3-{4-[bis-(4-hydroxy-phenyl)-carbamoyl]-phenyl}-propionic acid (11u). Inanother embodiment the NRBA or SERM compound of this invention isN,N-bis-(4-hydroxy-phenyl)-4-(3-hydroxy-propyl)-benzamide (11v). Inanother embodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-4-(3-hydroxypropyl)-N-(4-methoxyphenyl)-benzamide(11w). In another embodiment the NRBA or SERM compound of this inventionis 4-fluoro-N,N-bis(4-hydroxyphenyl)-2-(trifluoromethyl)-benzamide(11x). In another embodiment the NRBA or SERM compound of this inventionis 3-fluoro-N-(4-fluorophenyl)-4-hydroxy-N-(4-hydroxyphenyl)benzamide(11y). In another embodiment the NRBA or SERM compound of this inventionisN-(4-hydroxyphenyl)-4-methyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11z). In another embodiment the NRBA or SERM compound of this inventionis N,N-bis(4-hydroxyphenyl)-isonicotin-amide (11aa). In anotherembodiment the NRBA or SERM compound of this invention isN-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-isonicotinamide(11ab). In another embodiment, this invention provides a compositioncomprising a NRBA or SERM compound as described herein, or anycombination thereof.

In another embodiment, the SERM compound for use in the methods of thisinvention may be represented by the structure of formula XI:

wherein R₁ and R₂, which can be the same or different, are H or OH, R₃is OCH₂CH₂OH, OCH₂CH₂NR₄R₅, wherein R₄ and R₅, which can be the same ordifferent, are H, an alkyl group of 1 to about 4 carbon atoms or formstogether with the nitrogen a cyclic 5-8 membered ring; and theirpharmaceutically acceptable carrier, diluents, salts, esters, orN-oxides, and mixtures thereof.

In another embodiment, the SERM compound is toremifene

The term “alkyl” refers, in one embodiment, to a saturated aliphatichydrocarbon, including straight-chain, branched-chain and cyclic alkylgroups. In one embodiment, the alkyl group has 1-12 carbons. In anotherembodiment, the alkyl group has 1-7 carbons. In another embodiment, thealkyl group has 1-6 carbons. In another embodiment, the alkyl group has1-4 carbons. In another embodiment, the cyclic alkyl group has 3-8carbons. In another embodiment, the cyclic alkyl group has 3-12 carbons.In another embodiment, the branched alkyl is an alkyl substituted byalkyl side chains of 1 to 5 carbons. In another embodiment, the branchedalkyl is an alkyl substituted by haloalkyl side chains of 1 to 5carbons. The alkyl group may be unsubstituted or substituted by ahalogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thioand/or thioalkyl.

An “alkenyl” group refers, in another embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or more double bonds. The alkenyl group may have one doublebond, two double bonds, three double bonds, etc. In another embodiment,the alkenyl group has 2-12 carbons. In another embodiment, the alkenylgroup has 2-6 carbons. In another embodiment, the alkenyl group has 2-4carbons. Examples of alkenyl groups are ethenyl, propenyl, butenyl,cyclohexenyl, etc. The alkenyl group may be unsubstituted or substitutedby a halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido,nitro, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.

An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected fromhalogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio orthioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl,pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl,furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. Inone embodiment, the aryl group is a 4-8 membered ring. In anotherembodiment, the aryl group is a 4-12 membered ring(s). In anotherembodiment, the aryl group is a 6 membered ring. In another embodiment,the aryl group is a 5 membered ring. In another embodiment, the arylgroup is 2-4 fused ring system.

A “aldehyde” group refers, in one embodiment to an alkyl, or alkenylsubstituted by a formyl group, wherein the alkyl or alkenyl are asdefined hereinabove. In another embodiment, the aldehyde group is anaryl, or phenyl group substituted by a formyl group, wherein the aryl isas defined hereinabove. Examples of aldehydes are: formyl, acetal,propanal, butanal, pentanal, benzaldehyde. In another embodiment, thealdehyde group is a formyl group.

A “haloalkyl” group refers, in another embodiment, to an alkyl group asdefined above, which is substituted by one or more halogen atoms, e.g.by F, Cl, Br or I.

A “hydroxyl” group refers, in another embodiment, to an OH group. It isunderstood by a person skilled in the art that when R₁, R₂ or R₃ in thecompounds of the present invention is OR, then R is not OH.

In one embodiment, the term “halo” refers to a halogen, such as F, Cl,Br or I.

In another embodiment, the phrase “phenol” refers to an alcohol (OH)derivative of benzene.

A “heterocycle” group refers, in one embodiment, to a ring structurecomprising in addition to carbon atoms, sulfur, oxygen, nitrogen or anycombination thereof, as part of the ring. In another embodiment theheterocycle is a 3-12 membered ring. In another embodiment theheterocycle is a 6 membered ring. In another embodiment the heterocycleis a 5-7 membered ring. In another embodiment the heterocycle is a 4-8membered ring. In another embodiment, the heterocycle group may beunsubstituted or substituted by a halogen, haloalkyl, hydroxyl, alkoxy,carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO₂H, amino,alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl. In anotherembodiment, the heterocycle ring may be fused to another saturated orunsaturated cycloalkyl or heterocyclic 3-8 membered ring. In anotherembodiment, the heterocyclic ring is a saturated ring. In anotherembodiment, the heterocyclic ring is an unsaturated ring.

Reference to protected hydroxyl, in some embodiments, includes theincorporation of a substituent bonded to the oxygen moiety of thebenzene ring, wherein the substituent may be readily removed. In someembodiments, phenolic protecting groups may comprise a: methyl ether,methoxymethyl (MOM) ether, benzoyloxymethyl (BOM) ether,methoxyethoxymethyl (MEM) ether, 2-(trimethylsilyl)ethoxymethyl(SEM)ether, methylthiomethyl (MTM) ether, phenylthiomethyl (PTM) ether,azidomethyl ether, cyanomethyl ether, 2,2-dichloro-1,1-difluoroethylether, 2-chloroethyl ether, 2-bromoethyl ether, tetrahydropyranyl (THP)ether, 1-ethoxyethyl (EE) ether, phenacyl ether, 4-bromophenacyl ether,cyclopropylmethyl ether, allyl ether, propargyl ether, isopropyl ether,cyclohexyl ether, t-butyl ether, benzyl ether, 2,6-dimethylbenzyl ether,4-methoxybenzyl ether, o-nitrobenzyl ether, 2,6dichlorobenzyl ether,3,4dichlorobenzyl ether, 4-(dimethylamino)carbonylbenzyl ether,4-methylsulfinylbenzyl ether, 4-anthrylmethyl ether, 4-picolyl ether,heptafluoro-p-tolyl, tetrafluoro-4-pyridyl ether, trimethylsilyl (TMS)ether, t-butyldimethylsilyl (TBDMS) ether, t-butyldiphenylsilyl (TBDPS)ether, triisopropylsilyl (TIPS) ether, aryl formate, arylacetate, aryllevulinate, arylpivaloate, aryl benzoate, aryl 9-fluorenecarboxylate,aryl methyl carbonate, 1-adamantyl carbonate, t-butyl carbonate,4-methylsulfinylbenzyl carbonate, 2,4-dimethylpent-3-yl carbonate, aryl2,2,2trichloroethyl carbonate, aryl benzyl carbonate, aryl carbamate,dimethylphosphinyl ester (Dmp-OAr), dimethylphosphinothionyl ester(Mpt-OAr), diphenylphosphinothionyl ester (Dpt-OAr), arylmethanesulfonate, aryl toluenesulfonate or aryl2-formylbenzenesulfonate.

In one embodiment, this invention provides a NRBA or SERM compoundand/or analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,ester, polymorph, impurity or crystal or combinations thereof. In oneembodiment, this invention provides an analog of the NRBA or SERMcompound. In another embodiment, this invention provides a derivative ofthe NRBA or SERM compound. In another embodiment, this inventionprovides an isomer of the NRBA or SERM compound. In another embodiment,this invention provides a metabolite of the NRBA or SERM compound. Inanother embodiment, this invention provides a pharmaceuticallyacceptable salt of the NRBA or SERM compound. In another embodiment,this invention provides a pharmaceutical product of the NRBA or SERMcompound. In another embodiment, this invention provides a hydrate ofthe NRBA or SERM compound. In another embodiment, this inventionprovides an N-oxide of the NRBA or SERM compound. In another embodiment,this invention provides a prodrug of the NRBA or SERM compound. Inanother embodiment, this invention provides an ester of the NRBA or SERMcompound. In another embodiment, this invention provides a polymorph ofthe NRBA or SERM compound. In another embodiment, this inventionprovides a crystal of the NRBA or SERM compound. In another embodiment,this invention provides an impurity of the NRBA or SERM compound. Inanother embodiment, this invention provides composition comprising aNRBA or SERM compound, as described herein, or, in another embodiment, acombination of an analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, ester, impurity or crystal of the NRBA orSERM compounds of the present invention.

In one embodiment, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, the term “isomer” is meant to encompass opticalisomers of the NRBA or SERM compound. It will be appreciated by thoseskilled in the art that the NRBA or SERMs of the present inventioncontain at least one chiral center. Accordingly, the NRBA or SERMs usedin the methods of the present invention may exist in, and be isolatedin, optically-active or racemic forms. Some compounds may also exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereroisomeric form, or mixtures thereof, and use of these for anyapplication is to be considered within the scope of this invention.

In one embodiment, the NRBAs or SERMs are the pure (R)-isomers. Inanother embodiment, the NRBAs or SERMs are the pure (S)-isomers. Inanother embodiment, the NRBAs or SERMs are a mixture of the (R) and the(S) isomers. In another embodiment, the NRBAs or SERMs are a racemicmixture comprising an equal amount of the (R) and the (S) isomers. It iswell known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase), and such methods are to be considered as part of thisinvention. In some embodiments, synthesis of such racemic forms may beaccomplished by methods described and exemplified herein, or viaappropriate modification thereof, as will be understood by one skilledin the art.

In one embodiment, the NRBAs or SERMs are the pure (E)-isomers. Inanother embodiment, the NRBAs or SERMs are the pure (Z)-isomers. Inanother embodiment, the NRBAs or SERMs are a mixture of the (E) and the(Z) isomers.

The invention includes “pharmaceutically acceptable salts” of thecompounds of this invention, which may be produced, by reaction of acompound of this invention with an acid or base.

Suitable pharmaceutically-acceptable salts of amines of Formula I-XI maybe prepared from an inorganic acid or from an organic acid. In oneembodiment, examples of inorganic salts of amines are bisulfates,borates, bromides, chlorides, hemisulfates, hydrobromates,hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates),iodates, iodides, isothionates, nitrate, persulfates, phosphate,sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates,arylsulfonates, halogen substituted alkylsulfonates, halogen substitutedarylsulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilate,algenate, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, carboxilate, citrates, camphorates,camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates,calcium edetates, camsylates, carbonates, clavulanates, cinnamates,dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides,decanoates, enanthuates, ethanesulfonates, edetates, edisylates,estolates, esylates, fumarates, formates, fluorides, galacturonategluconates, glutamates, glycolates, glucorate, glucoheptanoates,glycerophosphates, gluceptates, glycollylarsanilates, glutarates,glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlicacids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoate,hydrofluorate, lactates, lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates, mitrates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, phenylacetate, pectinates, phenylpropionates, palmitates,pantothenates, polygalacturates, pyruvates, quinates, salicylates,succinates, stearates, sulfanilate, subacetates, tartarates,theophyllineacetates, p-toluenesulfonates (tosylates),trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates,triethiodide, tricarboxylates, undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orphenols may be selected from ammonium, alkali metals to include lithium,sodium, potassium, cesium; alkaline earch metals to include calcium,magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids orphenols may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolies, piperazines, procain,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In one embodiment, the pharmaceutically acceptable salt of a NRBAcompound comprising a piperidine ring is an HCl salt. In anotherembodiment, the pharmaceutically acceptable salt of a NRBA compoundcomprising a pyrrolidine ring is an HCl salt. In another embodiment, thepharmaceutically acceptable salt of a NRBA compound comprising amorpholine ring is an HCl salt. In another embodiment, thepharmaceutically acceptable salt of a NRBA compound comprising apiperazine ring is an HCl salt.

This invention provides, in some embodiments, derivatives of the NRBA orSERM compounds. In one embodiment, the term “derivatives” refers toether derivatives, acid derivatives, amide derivatives, esterderivatives or others, as known in the art. In another embodiment, thisinvention further includes hydrates of the NRBA or SERM compounds. Inone embodiment, the term “hydrate” refers to hemihydrate, monohydrate,dihydrate, trihydrate or others, as known in the art.

This invention provides, in other embodiments, metabolites of the NRBAor SERM compounds. In one embodiment, the term “metabolite” refers toany substance produced from another substance by metabolism or ametabolic process.

In some embodiments, a NRBA or SERM of this invention will comprise thecompounds listed in Table 1. In some embodiments, the NRBAs or SERMs ofthis invention will have an affinity for a nuclear hormone receptor,with varying affinity. In some embodiments of this invention, NRBAs orSERMs of this invention will vary in terms of their activity, forexample, some NRBAs or SERMs possessing greater anabolic activity, someexhibiting greater activity with regard to anti-estrogenic activity,etc. It is to be understood that all such NRBAs or SERMs are to beconsidered as part of this invention.

In some embodiments, the NRBAs or SERMs of this invention may exhibitaffinity for or binding to a nuclear receptor, which in someembodiments, is an estrogen receptor a and/or estrogen receptor βmolecule. In some embodiments, the NRBAs or SERMs of this invention mayexhibit agonist activity. In some embodiments, the NRBAs or SERMs ofthis invention may exhibit antagonist activity. Agonist and antagonistactivity for representative NRBAs are exemplified in the Examplesherein, wherein such agonist and/or antagonist activity under specificexperimental conditions is provided, representing only some embodimentsof this invention. It is to be understood that while the indicatedcompounds may exhibit a particular activity (for example, compound 3v isan agonist) under the experimental conditions employed, as a function,in some embodiments of the particular cells utilized, etc., suchcompounds may possess alternate, varied, or partial activity indifferent experimental settings. In some embodiments, the NRBAs or SERMsof this invention may exhibit agonist activity for a particularreceptor, and antagonist activity for a different receptor, or viceversa, or in some embodiments, the NRBAs or SERMs of this invention mayexhibit agonist activity for a particular receptor under certainexperimental conditions, yet exhibit antagonist activity for the samereceptor under different experimental conditions, or vice versa, or insome embodiments, the NRBAs or SERMs of this invention may exhibitagonist activity for a particular receptor in a particular tissue, yetexhibit antagonist activity for the same receptor in a different tissue,or vice versa, etc.

Steroid nuclear hormone receptors are known to have rapid,tissue-specific effects that are mediated by cell-surface and cytosolicreceptors through protein-protein interaction or phosphorylation ofkinases, which are known as non-genomic effects. For instance, SERMs areknown to have distinct rapid effects in the cardiovascular and centralnervous systems which may be mediated by distinct receptors. Putativereceptors for these non-genomic effects include a variety of G-proteincoupled receptors (GPCRs) such as GPR130 for SERMs, as well ascell-membrane associated or cytosolic nuclear receptors. NRBA and SERMsof this invention may also bind to receptors involved in thesenon-genomic effects allowing differential pharmacological exploitationof genomic, non-genomic, and tissue-selective steroid receptoractivities. As such these NRBA and SERMs may have a wide variety ofspecific and targeted steroid responses broadening their potential tohave beneficial medical properties

In some embodiments, a NRBA of this invention is a non-genomic agonist,or in some embodiments, a non-genomic antagonist, or in someembodiments, a non-genomic partial agonist of a nuclear receptor. Insome embodiments, the NRBAs of this invention are tissue selective,non-genomic nuclear receptors, such as for example, estrogen or androgenreceptor agonists, or in some embodiments, tissue selective, non-genomicnuclear receptor antagonists, or in some embodiments, tissue selective,non-genomic nuclear receptor partial agonists. In some embodiments, theNRBAs of this invention are non-selective non-genomic nuclear receptors,such as for example, estrogen or androgen receptor agonists, or in someembodiments, non-selective non-genomic nuclear receptor antagonists, orin some embodiments, non-selective non-genomic nuclear receptor partialagonists. In some embodiments, the NRBAs of this invention arenon-selective genomic nuclear receptors, such as for example, estrogenor androgen receptor agonists, or in some embodiments, antagonists, orin some embodiments, partial agonists. In some embodiments, the NRBAs ofthis invention are tissue selective genomic nuclear receptor modulators,such as for example, estrogen or androgen receptor agonists, or in someembodiments, antagonists, or in some embodiments, partial agonists. Insome embodiments, the NRBAs of this invention are genomic agents whichselectively transactivate nuclear receptor-regulated genes. In someembodiments, selective transactivation is in a tissue selective manner.In some embodiments, the NRBAs of this invention are genomic agentswhich selectively transrepress nuclear receptor-regulated genes. In someembodiments, selective tranrepression is in a tissue selective manner.

This invention provides, in other embodiments, pharmaceutical productsof the NRBA or SERM compounds. The term “pharmaceutical product” refers,in other embodiments, to a composition suitable for pharmaceutical use(pharmaceutical composition), for example, as described herein.

In one embodiment, this invention provides a method of binding any NRBAor SERM compound of this invention to an estrogen receptor or anestrogen related receptors, comprising the step of contacting anestrogen receptor with said NRBA or SERM. In another embodiment, thisinvention provides a method of binding any NRBA or SERM compound of thisinvention to a nuclear hormone receptor or one related thereto.

Pharmaceutical Compositions

In some embodiments, this invention provides methods of use whichcomprise administering a composition comprising the described compounds.As used herein, “pharmaceutical composition” means a “therapeuticallyeffective amount” of the active ingredient, i.e. the compound of thisinvention, together with a pharmaceutically acceptable carrier ordiluent. A “therapeutically effective amount” as used herein refers tothat amount which provides a therapeutic effect for a given conditionand administration regimen.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.In one embodiment, the present invention encompasses administering thecompounds of the present invention to a subject.

The pharmaceutical compositions containing the compounds of thisinvention can be administered to a subject by any method known to aperson skilled in the art, such as orally, parenterally,intravascularly, paracancerally, transmucosally, transdermally,intramuscularly, intranasally, intravenously, intradermally,subcutaneously, sublingually, intraperitonealy, intraventricularly,intracranially, intravaginally, by inhalation, rectally, intratumorally,or by any means in which the recombinant virus/composition can bedelivered to tissue (e.g., needle or catheter). Alternatively, topicaladministration may be desired for application to mucosal cells, for skinor ocular application. Another method of administration is viaaspiration or aerosol formulation.

In one embodiment, the pharmaceutical compositions are administeredorally, and are thus formulated in a form suitable for oraladministration, i.e. as a solid or a liquid preparation. Suitable solidoral formulations include tablets, capsules, pills, granules, pellets,powders, and the like. Suitable liquid oral formulations includesolutions, suspensions, dispersions, emulsions, oils and the like. Inone embodiment of the present invention, the SARM compounds areformulated in a capsule. In accordance with this embodiment, thecompositions of the present invention comprise in addition to a compoundof this invention and the inert carrier or diluent, a hard gelatincapsule.

In one embodiment, the micronized capsules comprise particles containinga compound of this invention, wherein the term “micronized” used hereinrefers to particles having a particle size is of less than 100 microns,or in another embodiment, less than 60 microns, or in anotherembodiment, less than 36 microns, or in another embodiment, less than 16microns, or in another embodiment, less than 10 microns, or in anotherembodiment, less than 6 microns.

Further, in another embodiment, the pharmaceutical compositions areadministered by intravenous, intraarterial, or intramuscular injectionof a liquid preparation. Suitable liquid formulations include solutions,suspensions, dispersions, emulsions, oils and the like. In oneembodiment, the pharmaceutical compositions are administeredintravenously, and are thus formulated in a form suitable forintravenous administration. In another embodiment, the pharmaceuticalcompositions are administered intraarterially, and are thus formulatedin a form suitable for intraarterial administration. In anotherembodiment, the pharmaceutical compositions are administeredintramuscularly, and are thus formulated in a form suitable forintramuscular administration.

Further, in another embodiment, the pharmaceutical compositions areadministered topically to body surfaces, and are thus formulated in aform suitable for topical administration. Suitable topical formulationsinclude gels, ointments, creams, lotions, drops and the like. Fortopical administration, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are prepared and applied as solutions, suspensions, oremulsions in a physiologically acceptable diluent with or without apharmaceutical carrier.

Further, in another embodiment, the pharmaceutical compositions areadministered as a suppository, for example a rectal suppository or aurethral suppository. Further, in another embodiment, the pharmaceuticalcompositions are administered by subcutaneous implantation of a pellet.In a further embodiment, the pellet provides for controlled release of acompound as herein described over a period of time. In a furtherembodiment, the pharmaceutical compositions are administeredintravaginally.

In another embodiment, the active compound can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1627-1633(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.363-366 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

In one embodiment, the compositions of this invention may include, acompound of this invention or any combination thereof, together with oneor more pharmaceutically acceptable excipients.

It is to be understood that this invention encompasses any embodiment ofa compound as described herein, which in some embodiments is referred toas “a compound of this invention”.

Suitable excipients and carriers may be, according to embodiments of theinvention, solid or liquid and the type is generally chosen based on thetype of administration being used. Liposomes may also be used to deliverthe composition. Examples of suitable solid carriers include lactose,sucrose, gelatin and agar. Oral dosage forms may contain suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. Liquiddosage forms may contain, for example, suitable solvents, preservatives,emulsifying agents, suspending agents, diluents, sweeteners, thickeners,and melting agents. Parenteral and intravenous forms should also includeminerals and other materials to make them compatible with the type ofinjection or delivery system chosen. Of course, other excipients mayalso be used.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, cyclodextrins,emulsions or suspensions, including saline and buffered media. Examplesof oils are those of petroleum, animal, vegetable, or synthetic origin,for example, peanut oil, soybean oil, mineral oil, olive oil, sunfloweroil, and fish-liver oil.

Parenteral vehicles (for subcutaneous, intravenous, intraarterial, orintramuscular injection) include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's and fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose, andthe like. Examples are sterile liquids such as water and oils, with orwithout the addition of a surfactant and other pharmaceuticallyacceptable adjuvants. In general, water, saline, aqueous dextrose andrelated sugar solutions, and glycols such as propylene glycols orpolyethylene glycol are preferred liquid carriers, particularly forinjectable solutions. Examples of oils are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil,mineral oil, olive oil, sunflower oil, and fish-liver oil.

In addition, the compositions may further comprise binders (e.g. acacia,cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, hydroxypropyl methyl cellulose, povidone), disintegratingagents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide,croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate),buffers (e.g., Tris-HCl., acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent absorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., cremophor, glycerol,polyethylene glycerol, benzlkonium chloride, benzyl benzoate,cyclodextrins, sobitan esters, stearic acids), anti-oxidants (e.g.,ascorbic acid, sodium metabisulfite, butylated hydroxyanisole),stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethylcellulose), viscosity increasing agents (e.g. carbomer, colloidalsilicon dioxide, ethyl cellulose, guar gum), sweetners (e.g. aspartame,citric acid), preservatives (e.g., Thimerosal, benzyl alcohol,parabens), coloring agents, lubricants (e.g. stearic acid, magnesiumstearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g.colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate,triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose,sodium lauryl sulfate), polymer coatings (e.g., poloxamers orpoloxamines), coating and film forming agents (e.g. ethyl cellulose,acrylates, polymethacrylates), and/or adjuvants.

In one embodiment, the pharmaceutical compositions provided herein arecontrolled release compositions, i.e. compositions in which the compoundof this invention is released over a period of time afteradministration. Controlled or sustained release compositions includeformulation in lipophilic depots (e.g. fatty acids, waxes, oils). Inanother embodiment, the composition is an immediate release composition,i.e. a composition in which all of the compound is released immediatelyafter administration.

In yet another embodiment, the pharmaceutical composition can bedelivered in a controlled release system. For example, the agent may beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit.Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:607 (1980);Saudek et al., N. Engl. J. Med. 321:674 (1989). In another embodiment,polymeric materials can be used. In yet another embodiment, a controlledrelease system can be placed in proximity to the therapeutic target,i.e., the brain, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 116-138 (1984). Other controlled release systems arediscussed in the review by Langer (Science 249:1627-1633 (1990).

The compositions may also include incorporation of the active materialinto or onto particulate preparations of polymeric compounds such aspolylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes,microemulsions, micelles, unilamellar or multilamellar vesicles,erythrocyte ghosts, or spheroplasts.) Such compositions will influencethe physical state, solubility, stability, rate of in vivo release, andrate of in vivo clearance.

Also comprehended by the invention are particulate compositions coatedwith polymers (e.g. poloxamers or poloxamines) and the compound coupledto antibodies directed against tissue-specific receptors, ligands orantigens or coupled to ligands of tissue-specific receptors.

Also comprehended by the invention are compounds modified by thecovalent attachment of water-soluble polymers such as polyethyleneglycol, copolymers of polyethylene glycol and polypropylene glycol,carboxymethyl cellulose, dextran, polyvinyl alcohol,polyvinylpyrrolidone or polyproline. The modified compounds are known toexhibit substantially longer half-lives in blood following intravenousinjection than do the corresponding unmodified compounds (Abuchowski etal., 1981; Newmark et al., 1982; and Katre et al., 1987). Suchmodifications may also increase the compounds solubility in aqueoussolution, eliminate aggregation, enhance the physical and chemicalstability of the compound, and greatly reduce the immunogenicity andreactivity of the compound. As a result, the desired in vivo biologicalactivity may be achieved by the administration of such polymer-compoundabducts less frequently or in lower doses than with the unmodifiedcompound.

The preparation of pharmaceutical compositions which contain an activecomponent is well understood in the art, for example by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients which are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the compounds of this invention or their physiologicallytolerated derivatives such as salts, esters, N-oxides, and the like aremixed with additives customary for this purpose, such as vehicles,stabilizers, or inert diluents, and converted by customary methods intosuitable forms for administration, such as tablets, coated tablets, hardor soft gelatin capsules, aqueous, alcoholic or oily solutions. Forparenteral administration, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are converted into a solution, suspension, or emulsion, ifdesired with the substances customary and suitable for this purpose, forexample, solubilizers or other.

An active component can be formulated into the composition asneutralized pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the freeamino groups of the polypeptide or antibody molecule), which are formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed from the free carboxyl groups can also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

For use in medicine, the salts of the compound will be pharmaceuticallyacceptable salts. Other salts may, however, be useful in the preparationof the compounds according to the invention or of their pharmaceuticallyacceptable salts. Suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid,maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid,citric acid, tartaric acid, carbonic acid or phosphoric acid.

In one embodiment, this invention provides pharmaceutical compositionscomprising a compound of this invention. In one embodiment, suchcompositions are useful for oral testosterone replacement therapy.

In one embodiment, this invention also provides a composition comprisingtwo or more compounds of this invention, or polymorphs, isomers,hydrates, salts, N-oxides, etc., thereof. The present invention alsorelates to compositions and a pharmaceutical compositions whichcomprises a compound of this invention alone or in combination with aprogestin or estrogen, or in another embodiment, chemotherapeuticcompound, osteogenic or myogenic compound, or other agents suitable forthe applications as herein described. In one embodiment, thecompositions of this invention will comprise a suitable carrier, diluentor salt.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, the compound of this invention is administered at adosage of 0.1-200 mg per day. In one embodiment, the compound of thisinvention is administered at a dose of 0.1-10 mg, or in anotherembodiment, 0.1-26 mg, or in another embodiment, 0.1-60 mg, or inanother embodiment, 0.3-16 mg, or in another embodiment, 0.3-30 mg, orin another embodiment, 0.6-26 mg, or in another embodiment, 0.6-60 mg,or in another embodiment, 0.76-16 mg, or in another embodiment, 0.76-60mg, or in another embodiment, 1-6 mg, or in another embodiment, 1-20 mg,or in another embodiment, 3-16 mg, or in another embodiment, 30-60 mg,or in another embodiment, 30-76 mg, or in another embodiment, 100-2000mg.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inone embodiment, the compound of this invention is administered at adosage of 1 mg. In another embodiment the compound of this invention isadministered at a dosage of 6 mg, 10 mg, 16 mg, 20 mg, 26 mg, 30 mg, 36mg, 40 mg, 46 mg, 60 mg, 66 mg, 60 mg, 66 mg, 70 mg, 76 mg, 80 mg, 86mg, 90 mg, 96 mg or 100 mg.

In one embodiment, the present invention provides methods of usecomprising the administration of a pharmaceutical composition comprisinga) any embodiment of a compound as described herein; and b) apharmaceutically acceptable carrier or diluent; which is to beunderstood to include an analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, N-oxide, hydrate or any combinationthereof of a compound as herein described.

In some embodiments, the present invention provides methods of use of apharmaceutical composition comprising a) any embodiment of the compoundsas described herein, including an analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate thereof or any combination thereof; b) apharmaceutically acceptable carrier or diluent; c) a flow-aid; and d) alubricant.

In another embodiment, the present invention provides methods of use ofa pharmaceutical composition comprising a) any embodiment of thecompounds as described herein, including an analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate thereof or any combination thereof; b) lactosemonohydrate; c) microcrystalline cellulose; d) magnesium stearate; ande) colloidal silicon dioxide.

In some embodiments, the methods of this invention make use ofcompositions comprising compounds of this invention, which offer theadvantage that the compounds are nonsteroidal ligands for the androgenreceptor, and exhibit anabolic activity in vivo. According to thisaspect, such compounds are unaccompanied by serious side effects,provide convenient modes of administration, and lower production costsand are orally bioavailable, lack significant cross-reactivity withother undesired steroid receptors, and may possess long biologicalhalf-lives.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In one embodiment, the compositions for administration may be sterilesolutions, or in other embodiments, aqueous or non-aqueous, suspensionsor emulsions. In one embodiment, the compositions may comprise propyleneglycol, polyethylene glycol, injectable organic esters, for exampleethyl oleate, or cyclodextrins. In another embodiment, compositions mayalso comprise wetting, emulsifying and/or dispersing agents. In anotherembodiment, the compositions may also comprise sterile water or anyother sterile injectable medium.

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention, as described herein. In one embodiment, use of acompound of this invention or a composition comprising the same, willhave utility in inhibiting, suppressing, enhancing or stimulating adesired response in a subject, as will be understood by one skilled inthe art. In another embodiment, the compositions may further compriseadditional active ingredients, whose activity is useful for theparticular application for which the compound of this invention is beingadministered.

In some embodiments, the methods of this invention make use ofcompositions comprising compounds of this invention, which offer theadvantage that the compounds are nonsteroidal ligands for the androgenreceptor, and exhibit anabolic activity in vivo. According to thisaspect, such compounds are unaccompanied by serious side effects,provide convenient modes of administration, and lower production costsand are orally bioavailable, lack significant cross-reactivity withother undesired steroid receptors, and may possess long biologicalhalf-lives.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In one embodiment, the compositions for administration may be sterilesolutions, or in other embodiments, aqueous or non-aqueous, suspensionsor emulsions. In one embodiment, the compositions may comprise propyleneglycol, polyethylene glycol, injectable organic esters, for exampleethyl oleate, or cyclodextrins. In another embodiment, compositions mayalso comprise wetting, emulsifying and/or dispersing agents. In anotherembodiment, the compositions may also comprise sterile water or anyother sterile injectable medium.

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention. In one embodiment, use of a compound of thisinvention or a composition comprising the same, will have utility ininhibiting, suppressing, enhancing or stimulating a desired response ina subject, as will be understood by one skilled in the art. In anotherembodiment, the compositions may further comprise additional activeingredients, whose activity is useful for the particular application forwhich the compound of this invention is being administered.

In some embodiments, the compositions will further comprise a5a-Reductase Inhibitors, a SARM or SARMs, a selective estrogen receptormodulator (SERM), an aromatase inhibitor, such as but not limited toanastrazole, exemestane, or letrozole; a GnRH agonist or antagonist, asteroidal or nonsteroidal GR ligand, a steroidal or nonsteroidal PRligand, a steroidal or nonsteroidal AR antagonist, a17-aldoketoreductase inhibitor or 17b-hydroxysteroid dehydrogenaseinhibitor. Such compositions may be used, in some embodiments, fortreating a hormone dependent condition, such as, for example,infertility, neoplasia of a hormone-responsive cancer, for example, agonadal cancer, or a urogenital cancer.

In some embodiments, the composition will comprise the compounds asdescribed herein, as well as another therapeutic compound, includinginter alia, a 5ARI such as finasteride, dutasteride, izonsteride; otherSARMs, such as, RU-58642, RU-56279, WS9761 A and B, RU-59063, RU-58841,bexlosteride, LG-2293, L-245976, LG-121071, LG-121091, LG-121104,LGD-2226, LGD-2941, YM-92088, YM-175735, LGD-1331, BMS-357597,BMS-391197, S-40503, BMS-482404, EM-4283, EM-4977, BMS-564929,BMS-391197, BMS-434588, BMS-487745, BMS-501949, SA-766, YM-92088,YM-580, LG-123303, LG-123129, PMCol, YM-175735, BMS-591305, BMS-591309,BMS-665139, BMS-665539, CE-590, 116BG33, 154BG31, arcarine, ACP-105;SERMs, such as tamoxifene, 4-hydroxytamoxifene, idoxifene, toremifene,ospemifene, droloxifene, raloxifene, arzoxifene, bazedoxifene, PPT(1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN, lasofoxifene,pipendoxifene, EM-800, EM-652, nafoxidine, zindoxifene, tesmilifene,miproxifene phosphate, RU 58,688, EM 139, ICI 164,384, ICI 182,780,clomiphene, MER-25, diethylstibestrol, coumestrol, genistein, GW5638,LY353581, zuclomiphene, enclomiphene, delmadinone acetate, DPPE,(N,N-diethyl-2-{4-(phenylmethyl)-phenoxy}ethanamine), TSE-424, WAY-070,WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, WAY-244,ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380,BE-381, WAY-358, [18F]FEDNP, LSN-500307, AA-102, Ban zhi lian, CT-101,CT-102, VG-101; GnRH agonists or antagonists, such as, leuprolide,goserelin, triptorelin, alfaprostol, histrelin, detirelix, ganirelix,antide iturelix, cetrorelix, ramorelix, ganirelix, antarelix, teverelix,abarelix, ozarelix, sufugolix, prazarelix, degarelix, NBI-56418,TAK-810, acyline; FSH agonist/antagonist, LH agonist/antagonists,aromatase inhibitors, such as, letrozole, anastrazole, atamestane,fadrozole, minamestane, exemestane, plomestane, liarozole, NKS-01,vorozole, YM-511, finrozole, 4-hydroxyandrostenedione, aminogluethimide,rogletimide; Steroidal or nonsteroidal glucocorticoid receptor ligands,such as, ZK-216348, ZK-243149, ZK-243185, LGD-5552, mifepristone,RPR-106541, ORG-34517, GW-215864X, Sesquicillin, CP-472555, CP-394531,A-222977, AL-438, A-216054, A-276575, CP-394531, CP-409069, UGR-07;Steroidal or nonsteroidal progesterone receptor ligands; Steroidal ornonsteroidal AR antagonists such as flutamide, hydroxyflutamide,bicalutamide, nilutamide, hydroxysteroid dehydrogenase inhibitors, PPARligand such as bezafibrate, fenofibrate, gemfibrozil; PPARγ ligands suchas darglitazone, pioglitazone, rosiglitazone, isaglitazone,rivoglitazone, netoglitazone; Dual acting PPAR ligands, such asnaveglitazar, farglitazar, tesaglitazar, ragaglitazar, oxeglitazar,PN-2034, PPAR δ; a 17-ketoreductase inhibitors, 3β-DHΔ4,6-isomeraseinhibitors, 3β-DHΔ4,5-isomerase inhibitors, 17,20 desmolase inhibitors,p450c17 inhibitors, p450ssc inhibitors, 17,20-lyase inhibitors, orcombinations thereof.

In some embodiments, the compositions will further comprise Ghrelinreceptor ligand or growth hormone analogues and secretagogues, IGF-1,IGF-1 analogues and secretagogues, Myostatin Analogues, ProteasomeInhibitors, Androgenic/Anabolic Steroid, EnbrelMelanocortin 4 ReceptorAgonist, Insulins, or combinations thereof. Such compositions may beused, in some embodiments, for treating sarcopenia or a musculoskeletalcondition.

In some embodiments, the composition will comprise the compounds asdescribed herein, as well as another therapeutic compound, includinginter alia, Ghrelin receptor ligand or growth hormone analogues andsecretagogues, such as, pralmorelin, examorelin, tabimorelin,capimorelin, capromorelin, ipamorelin, EP-01572, EP-1572, JMV-1843, anandrogenic/Anabolic Steroid such as Testosterone/Oxandrolone; amelanocortin 4 receptor agonist, such as Bremelanotide, a Ghrelin oranalogue thereof, such as human ghrelin, CYT-009-GhrQb, L-692429,GHRP-6, SK&F-110679, U-75799E), leptin (metreleptin, pegylated leptin; aleptin receptor agonist, such as LEP(116-130), OB3, [D-Leu4]-OB3,rAAV-leptin, AAV-hOB, rAAVhOB; an insulin (short-, intermediate-, andlong acting formulations; a cortisol or corticosteroid, or a combinationthereof.

The invention contemplates, in some embodiments, administration ofcompositions comprising the individual agents, administered separatelyand by similar or alternative routes, formulated as appropriately forthe route of administration. The invention contemplates, in someembodiments, administration of compositions comprising the individualagents, administered in the same formulation. The inventioncontemplates, in some embodiments, staggered administration, concurrentadministration, of administration of the various agents over a course oftime, however, their effects are synergistic in the subject.

It is to be understood that any of the above means, timings, routes, orcombinations thereof, of administration of two or more agents is to beconsidered as being encompassed by the phrase “administered incombination”, as described herein.

In one embodiment, the compound of this invention is administered incombination with an anti-cancer agent. In one embodiment, theanti-cancer agent is a monoclonal antibody. In some embodiments, themonoclonal antibodies are used for diagnosis, monitoring, or treatmentof cancer. In one embodiment, monoclonal antibodies react againstspecific antigens on cancer cells. In one embodiment, the monoclonalantibody acts as a cancer cell receptor antagonist. In one embodiment,monoclonal antibodies enhance the patient's immune response. In oneembodiment, monoclonal antibodies act against cell growth factors, thusblocking cancer cell growth. In one embodiment, anti-cancer monoclonalantibodies are conjugated or linked to anti-cancer drugs, radioisotopes,other biologic response modifiers, other toxins, or a combinationthereof. In one embodiment, anti-cancer monoclonal antibodies areconjugated or linked to a compound of this invention as describedhereinabove.

In another embodiment, the present invention includes compounds andcompositions in which a compound of the invention is either combinedwith, or covalently bound to, an agent bound to a targeting agent, suchas a monoclonal antibody (e.g., a murine or humanized monoclonalantibody). In one embodiment, the agent bound to a targeting agent is acytotoxic agent. It will be appreciated that the latter combination mayallow the introduction of cytotoxic agents into for example cancer cellswith greater specificity. Thus, the active form of the cytotoxic agent(i.e., the free form) will be present only in cells targeted by theantibody. Of course, the compounds of the invention may also be combinedwith monoclonal antibodies that have therapeutic activity againstcancer.

In one embodiment, the compound is administered in combination with aselective tyrosine kinase inhibitor. In some embodiments, the selectivetyrosine kinase inhibitor inhibits catalytic sites of cancer promotingreceptors thereby inhibiting tumor growth. In one embodiment, aselective tyrosine kinase inhibitor modulates growth factor signaling.In some embodiments, the selective tyrosine kinase inhibitor targetsEGFR (ERB B/HER) family members. In one embodiment, the selectivetyrosine kinase inhibitor is a BCR-ABL tyrosine kinase inhibitor. In oneembodiment, the selective tyrosine kinase inhibitor is an epidermalgrowth factor receptor tyrosine kinase inhibitor. In one embodiment, theselective tyrosine kinase inhibitor is a vascular endothelial growthfactor tyrosine kinase inhibitor. In one embodiment, the selectivetyrosine kinase inhibitor is a Platelet Derived Growth Factor (PDGF)inhibitor.

In one embodiment, the compound is administered in combination with acancer vaccine. In one embodiment, the cancer vaccine is a therapeuticvaccine thus, treating an existing cancer. In some embodiments, thecancer vaccine is a prophylactic vaccine thus, preventing thedevelopment of cancer. In one embodiment, both types of vaccines havethe potential to reduce the burden of cancer. In one embodiment,treatment or therapeutic vaccines are administered to cancer patientsand are designed to strengthen the body's natural defenses againstcancers that have already developed. In one embodiment, therapeuticvaccines may prevent additional growth of existing cancers, prevent therecurrence of treated cancers, or eliminate cancer cells not killed byprior treatments. In some embodiments, prevention or prophylacticvaccines are administered to healthy individuals and are designed totarget cancer in individuals who present high risk for the disease. Inone embodiment, the cancer vaccine is an antigen/adjuvant vaccine. Inone embodiment, the cancer vaccine is a whole cell tumor vaccine. In oneembodiment, the cancer vaccine is a dendritic cell vaccine. In oneembodiment, the cancer vaccine comprises viral vectors and/or DNAvaccines. In one embodiment, the cancer vaccine is an idiotype vaccine.

In one embodiment, the compound is administered in combination with ananti-cancer chemotherapeutic agent. In one embodiment, the anti-cancerchemotherapeutic agent is an alkylating agent, such as but not limitedto cyclophosphamide. In one embodiment, the anti-cancer chemotherapeuticagent is a cytotoxic antibiotic such as but not limited to doxorubicin.In one embodiment, the anti-cancer chemotherapeutic agent is anantimetabolite, such as but not limited to methotrexate. In oneembodiment, the anti-cancer chemotherapeutic agent is a vinca alkaloid,such as but not limited to vindesine. In some embodiments, theanti-cancer chemotherapeutic agents include platinum compounds such asbut not limited to carboplatin, and taxanes such as docetaxel. In oneembodiment, the anti-cancer chemotherapeutic agent is an aromataseinhibitor such as but not limited to anastrazole, exemestane, orletrozole.

In one embodiment, the compound is administered in combination with aBax activity modulator such as alisol B acetate. In one embodiment, thecompound is administered in combination with an angiotensin II receptorblocker such as losartan. In one embodiment, the compound isadministered in combination with selenium, green tea cachecins, sawpalmetto, lycopene, vitamin D, dietary soy, genistein or isoflavone.

In one embodiment, the compound is administered in combination withantineoplastic agents, such as alkylating agents, antibiotics, hormonalantineoplastics and antimetabolites. Examples of useful alkylatingagents include alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines, such as a benzodizepa, carboquone, meturedepaand uredepa; ethylenimines and methylmelamines such as altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophos-phoramide and trimethylolmelamine; nitrogen mustardssuch as chlorambucil, chlomaphazine, cyclophosphamide, estramustine,iphosphamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichine, phenesterine, prednimustine, trofosfamide, anduracil mustard; nitroso ureas, such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine, dacarbazine,mannomustine, mitobronitol, mitolactol and pipobroman. More such agentswill be known to those having skill in the medicinal chemistry andoncology arts.

In some embodiments, other agents suitable for combination with thecompounds of this invention include protein synthesis inhibitors such asabrin, aurintricarboxylic acid, chloramphenicol, colicin E3,cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin,ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylylmethylene diphosphonate and guanylyl imidodiphosphate, kanamycin,kasugamycin, kirromycin, and O-methyl threonine, modeccin, neomycin,norvaline, pactamycin, paromomycine, puromycin, ricin, α-sarcin, shigatoxin, showdomycin, sparsomycin, spectinomycin, streptomycin,tetracycline, thiostrepton and trimethoprim. Inhibitors of DNAsynthesis, including alkylating agents such as dimethyl sulfate,mitomycin C, nitrogen and sulfur mustards, MNNG and NMS; intercalatingagents such as acridine dyes, actinomycins, adriamycin, anthracenes,benzopyrene, ethidium bromide, propidium diiodide-intertwining, andagents such as distamycin and netropsin, can also be combined withcompounds of the present invention in pharmaceutical compositions. DNAbase analogs such as acyclovir, adenine, β-1-D-arabinoside,amethopterin, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine,azaserine, 6-azauracil, 2′-azido-2′-deoxynucliosides,5-bromodeoxycytidine, cytosine, β-1-D-arabinoside, diazooxynorleucine,dideoxynucleosides, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine,5-fluorouracil, hydroxyurea and 6-mercaptopurine also can be used incombination therapies with the compounds of the invention. Topoisomeraseinhibitors, such as coumermycin, nalidixic acid, novobiocin and oxolinicacid, inhibitors of cell division, including colcemide, colchicine,vinblastine and vincristine; and RNA synthesis inhibitors includingactinomycin D, α-amanitine and other fungal amatoxins, cordycepin(3′-deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine,streptovaricin and streptolydigin also can be combined with thecompounds of the invention to provide pharmaceutical compositions.

In one embodiment, the compound is administered in combination with avaccine for prostate cancer, Alisol B acetate, angiotensin II receptorblocker, or others known in the art. In one embodiment, the compound isadministered in combination with an agent to decrease prostate (benignor malignant) hypertrophy, such as, for example, Selenium, green teacachecins, saw palmetto, lycopene, vitamin D, dietary soy, genistein andisoflavone food product and others.

In one embodiment, the compound is administered in combination with animmunomodulating agent. In one embodiment, the immunomodulating agent isan immunosuppressive agent. In one embodiment, immunosuppressive agentscomprise corticosteroids, cyclosporine, azathioprine, methotrexate,cyclophosphamide, tacrolimus-FK-506, anti-thymocyte globulin,mycophenylate moeftil, or a combination thereof. In one embodiment, thecorticosteroid is a glucocorticoid.

In one embodiment, the immunomodulating agent is an immunostimulatoryagent. In one embodiment, the immunostimulatory agent is a specificimmunostimulator thus, provides antigenic specificity during an immuneresponse, such as a vaccine or any antigen. In one embodiment, theimmunostimulatory agent is a non-specific immunostimulator thus, actingirrespective of antigenic specificity to augment immune response ofother antigen or stimulate components of the immune system withoutantigenic specificity. In one embodiment, the non-specificimmunostimulator is Freund's complete adjuvant. In one embodiment, thenon-specific immunostimulator is Freund's incomplete adjuvant. In oneembodiment, the non-specific immunostimulator is a montanide ISAadjuvant. In one embodiment, the non-specific immunostimulator is aRibi's adjuvant. In one embodiment, the non-specific immunostimulator isa Hunter's TiterMax. In one embodiment, the non-specificimmunostimulator is an aluminum salt adjuvant. In one embodiment, thenon-specific immunostimulator is a nitrocellulose-adsorbed protein. Inone embodiment, the non-specific immunostimulator is a Gerbu Adjuvant.

In one embodiment, the compound is administered in combination with anagent, which treats bone diseases, disorders or conditions, such asosteoporosis, bone fractures, etc., and this invention comprises methodsof treating the same, by administering the compounds as hereindescribed, alone or in combination with other agents.

In one embodiment, bone turnover markers have been demonstrated as aneffective, validated tool for the clinical scientist to monitor boneactivity. In another embodiment, urinary hydroxyproline, serum alkalinephosphatase, tartrate-resistant acid phosphatase, and osteocalcinlevels, along with the urinary calcium-creatinine ratio are used as boneturnover markers. In another embodiment osteocalcin levels is used as abone formation marker. In another embodiment c-telopeptide is used as abone resorption marker.

In one embodiment, this invention provides for the treatment,prevention, suppression or inhibition of, or the reduction of the riskof developing a skeletal-related event (SRE), such as bone fractures,surgery of the bone, radiation of the bone, spinal cord compression, newbone metastasis, bone loss, or a combination thereof in a subject withcancer, comprising administering to the a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof. The invention relates, inter alia to treatment ofan SRE with the compound of this invention in a subject with prostatecancer undergoing or having undergone androgen deprivation therapy(ADT).

In one embodiment, the skeletal-related events treated using the methodsprovided herein and/or utilizing the compositions provided herein, arefractures, which in one embodiment, are pathological fractures,non-traumatic fractures, vertebral fracture, non-vertebral fractures,morphometric fractures, or a combination thereof. In some embodiments,fractures may be simple, compound, transverse, greenstick, or comminutedfractures. In one embodiment, fractures may be to any bone in the body,which in one embodiment, is a fracture in any one or more bones of thearm, wrist, hand, finger, leg, ankle, foot, toe, hip, collar bone, or acombination thereof.

In another embodiment, the methods and/or compositions provided herein,are effective in treatment, prevention, suppression, inhibition orreduction of the risk of skeletal-related events such as pathologicfractures, spinal cord compression, hypercalcemia, bone-related pain, ortheir combination.

In another embodiment, the skeletal-related events sought to be treatedusing the methods provided herein and/or utilizing the compositionsprovided herein, comprise the necessity for bone surgery and/or boneradiation, which in some embodiments, is for the treatment of painresulting in one embodiment from bone damage, or nerve compression. Inanother embodiment, the skeletal-related events sought to be treatedusing the methods provided herein and/or utilizing the compositionsprovided herein, comprise spinal cord compression, or the necessity forchanges in antineoplastic therapy, including changes in hormonaltherapy, in a subject. In some embodiments, skeletal-related eventssought to be treated using the methods provided herein and/or utilizingthe compositions provided herein, comprise treating, suppressing,preventing, reducing the incidence of, or delaying progression orseverity of bone metastases, or bone loss. In one embodiment, bone lossmay comprise osteoporosis, osteopenia, or a combination thereof. In oneembodiment, skeletal-related events may comprise any combination of theembodiments listed herein.

In one embodiment, the methods provided herein and/or utilizing thecompositions provided herein, are effective in reducing metastases tothe bone, such as in terms of number of foci, the size of foci, or acombination thereof. According to this aspect of the invention and inone embodiment, provided herein is a method of preventing or inhibitingcancer metastasis to bone in a subject, comprising the step ofadministering to the subject a composition comprising toremifene,raloxifene, tamoxifen or an analogue, functional derivative, metaboliteor a combination thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, such metabolites may comprise ospemifene, fispemifeneor their combination. In one embodiment, the cancer is prostate cancer.

A person skilled in the art would readily recognize that changes in theantineoplastic therapy according to the methods provided herein,utilizing the compositions provided herein may be conducted as afunction of, or adjusted or varied as a function of, inter-alia, theseverity of the underlying disease, the source of the underlyingdisease, the extent of the patients' pain and source of the patients'pain, as well as the stage of the disease. The therapeutic changes mayinclude in certain embodiments, changes in the route of administration(e.g. intracavitarily, intraartiarly, intratumoraly etc.), forms of thecompositions administered (e.g. tablets, elixirs, suspensions etc.),changes in dosage and the like. Each of these changes are wellrecognized in the art and are encompassed by the embodiments providedherein.

In one embodiment, the skeletal-related events are a result of cancertherapy. In one embodiment, the skeletal-related events are a result ofhormone deprivation therapy, while in another embodiment, they are aproduct of androgen deprivation therapy (ADT).

In one embodiment, the compounds of this invention are useful inprevention or reversal of androgen-deprivation therapy (ADT) inducedside effects such as reduced muscle mass, reduced muscle strength,frailty, hypogonadism, osteoporosis, osteopenia, decreased BMD and/ordecreased bone mass.

In males, while the natural decline in sex-hormones at maturity (directdecline in androgens as well as lower levels of estrogens derived fromperipheral aromatization of androgens) is associated with the frailty ofbones, this effect is more pronounced in males who have undergoneandrogen deprivation therapy.

Such agents for combined use may comprise a SERM, as herein described, abisphosphonate, for example, alendronate, tiludroate, clodroniate,pamidronate, etidronate, alendronate, zolendronate, cimadronate,neridronate, minodronic acid, ibandronate, risedronate, homoresidronate,a calcitonin, for example, salmon, Elcatonin, SUN-8577, TJN-135; aVitamin D or derivative (ZK-156979); a Vitamin D receptor ligand oranalogues thereof, such as calcitriol, topitriol, ZK-150123, TEI-9647,BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299, DP-035, an estrogen, estrogenderivative, or conjugated estrogen; an antiestrogen, progestin,synthetic estrogen/progestin; a RANK ligand mAb, for example, denosumabor AMG162 (Amgen); an ανβ3 integrin receptor antagonist; an osteoclastvacuolar ATPase inhibitor; an antagonist of VEGF binding to osteoclastreceptors; a calcium receptor antagonist; PTh (parathyroid hormone) oranalogues thereof, PTHrP analogues (parathyroid hormone-relatedpeptide), Cathepsin K inhibitors (AAE581); Strontium ranelate; Tibolone;HCT-1026, PS K3471; Gallium maltolate; Nutropin AQ; Prostaglandins, p38protein kinase inhibitor; a bone morphogenetic protein; an inhibitor ofBMP antagonism, an. HMG-CoA reductase inhibitor, a Vitamin K orderivative, an antiresorptive, an Ipriflavone, a fluoride salt, dietarycalcium supplement, Osteoprotegerin, or any combination thereof. In oneembodiment, the combined administration of a SARM as herein described,Osteoprotegerin and parathyroid hormone is contemplated for treating anydisease, disorder or condition of the bone.

In one embodiment, the immunomodulating agent is an anti-inflammatoryagent. In one embodiment, the anti-inflammatory agent is a non-steroidalanti-inflammatory agent. In one embodiment, the non-steroidalanti-inflammatory agent is a cox-1 inhibitor. In one embodiment, thenon-steroidal anti-inflammatory agent is a cox-2 inhibitor. In oneembodiment, the non-steroidal anti-inflammatory agent is a cox-1 andcox-2 inhibitor. In some embodiments, non-steroidal anti-inflammatoryagents include but are not limited to aspirin, salsalate, diflunisal,ibuprofen, fenoprofen, flubiprofen, fenamate, ketoprofen, nabumetone,piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin,etodolac, ketorolac, oxaprozin, or celecoxib. In one embodiment, theanti-inflammatory agent is a steroidal anti-inflammatory agent. In oneembodiment, the steroidal anti-inflammatory agent is a corticosteroid.

In one embodiment, the immunomodulating agent is an anti-rheumaticagent. In one embodiment, the anti-rheumatic agent is a non-steroidalanti-inflammatory agent. In one embodiment, the anti-rheumatic agent isa corticosteroid. In one embodiment, the corticosteroid is prednisone ordexamethasone. In one embodiment, the anti-rheumatic agent is a diseasemodifying anti-rheumatic drug. In one embodiment, the disease modifyinganti-rheumatic drug is a slow-acting anti-rheumatic drug. In oneembodiment, the disease modifying anti-rheumatic drug is an antimalarialagent. In one embodiment, disease modifying anti-rheumatic drugs includebut are not limited to chloroquine, hydroxychloroquine, methotrexate,sulfasalazine, cyclosporine, azathioprine, cyclophosphamide,azathioprine, sulfasalazine, penicillamine, aurothioglucose, gold sodiumthiomalate, or auranofin. In one embodiment, the anti-rheumatic agent isan immunosuppressive cytotoxic drug. In one embodiment,immunosuppressive cytotoxic drugs include but are not limited tomethotrexate, mechlorethamine, cyclophosphamide, chlorambucil, orazathioprine.

In one embodiment, the compound is administered in combination with anantidiabetic agent. In one embodiment, the antidiabetic agent is asulfonylurea. In one embodiment, sulfonylureas include but are notlimited to tolbutamide, acetohexamide, tolazamide, chlorpropamide,glipizide, glyburide, glimepiride, or gliclazide. In one embodiment, theantidiabetic agent is a meglitinide. In one embodiment, meglitinidesinclude but are not limited to prandin or nateglinide. In oneembodiment, the antidiabetic agent is a biguanide. In one embodiment,biguanides include but are not limited to metformin In one embodiment,the antidiabetic agent is a thiazolidinedione. In one embodiment,thiazolidinediones include but are not limited to rosiglitazone,pioglitazone, or troglitazone. In one embodiment, the antidiabetic agentis an alpha glucosidase inhibitor. In one embodiment, alpha glucosidaseinhibitors include but are not limited to miglitol or acarbose. In oneembodiment, the antidiabetic agent is PPARα/γ ligand,dipeptidylpeptidase 4 (DPP-4) inhibitor, SGLT (sodium-dependent glucosetransporter 1) inhibitor, or FBPase (fructose 1,6-bisphosphatase)inhibitor. In one embodiment, the antidiabetic agent is insulin. In oneembodiment, the insulin is rapid-acting insulin. In one embodiment, theinsulin is short-acting insulin. In one embodiment, the insulin isintermediate-acting insulin. In one embodiment, the insulin isintermediate- and short-acting insulin mixtures. In one embodiment, theinsulin is long-acting insulin. In one embodiment, the antidiabeticagents are inhibitors of fatty acid binding protein (aP2) such as thosedisclosed in U.S. Ser. No. 09/519,079 filed Mar. 6, 2000, glucagon-likepeptide-1 (GLP-1), and dipeptidyl peptidase IV (DPP4) inhibitors such asthose disclosed in WO 0168603, which are incorporated by reference.

In one embodiment, the compound is administered in combination with anagent treating the nervous system. In one embodiment, the agent treatingthe nervous system is an agent treating the autonomic nervous system. Inone embodiment, the agent treating the autonomic nervous system is anadrenomimetic drug. In one embodiment, the adrenomimetic drug is abeta-adrenoceptor agonist, alpha-adrenoceptor agonist, or a combinationthereof. In one embodiment, the adrenomimetic drug is a catecholamine.In one embodiment, adrenomimetic drugs include but are not limited toisoproterenol, norepinephrine, epinephrine, amphetamine, ephedrine, ordopamine. In one embodiment, the adrenomimetic drug is a directly actingadrenomimetic drug. In some embodiments, directly acting adrenomimeticdrugs include but are not limited to phenylephrine, metaraminol, ormethoxamine.

In one embodiment, the agent treating the autonomic nervous system is anadrenoceptor antagonist. In one embodiment, the adrenoceptor antagonistis a haloalkylamine, imidazoline, or quinazoline. In one embodiment,haloalkylamines include but are not limited to phenoxybenzamine. In oneembodiment, imidazolines include but are not limited to phentolamine ortolazoline. In one embodiment, quinazolines include but are not limitedto prazosine, terazosin, doxazosin, or trimazosin. In one embodiment,the adrenoceptor antagonist has a combined alpha and beta blockingactivity. In one embodiment, the combined alpha and beta blocking agentis labetalol, bucindolol, carvedilol, or medroxalol.

In one embodiment, the agent treating the autonomic nervous system is acholinomimetic agent. In one embodiment, the cholinomimetic agent is adirect-acting parasympathomimetic drug. In one embodiment, direct-actingparasympathomimetic drugs include but are not limited to methacholine,pilocarpine, carbachol, or bethanechol.

In one embodiment, the agent treating the autonomic nervous system is acholinesterase inhibitor. In one embodiment, the cholinesteraseinhibitor is a quaternary ammonium agent. In one embodiment, quaternaryammonium agents include but are not limited to edrophonium orambenonium. In one embodiment, the cholinesterase inhibitor is acarbamate such as physostigmine, pyridostigmine, neostigmine, orrivastigmine. In one embodiment, the cholinesterase inhibitor is anorganophosphate agent. In one embodiment, the inhibitor targetsacetylcholine in the central nervous system such as tacrine, donepezil,or galanthamine.

In one embodiment, the agent treating the autonomic nervous system is amuscarinic blocking agent. In one embodiment, the muscarinic blockingagent is a belladonna alkaloid such as atropine or scopolamine.

In one embodiment, the agent treating the autonomic nervous system is agangilionic blocking agent. In one embodiment, gangilionic blockingagents include but are not limited to nicotine, trimethaphan, ormecamylamine.

In one embodiment, the agent treating the nervous system is an agenttreating the central nervous system. In one embodiment, the agenttreating the central nervous system is a local anesthetic agent. In oneembodiment, local anesthetic agents include but are not limited tobenzocaine, chloroprocaine, cocaine, procaine, bupivacaine,levobupivacaine, lidocaine, mepivacaine, prilocalne, or ropivacaine. Inone embodiment, the agent treating the central nervous system is ageneral anaesthetic agent. In one embodiment, general anesthetic agentsinclude but are not limited to esflurane, sevoflurane, isoflurane,halothane, enflurane, methoxyflurane, xenon, propofol, etomidate,methohexital, midazolam, diazepamor, ketamine, thiopentone/thiopental,or lidocaine/prilocalne.

In one embodiment, the agent treating the central nervous system is ananalgesic agent. In some embodiments, analgesic agents include but arenot limited to paracetamol or non-steroidal anti-inflammatory agent. Insome embodiments, analgesic agents include opiates or morphinomimeticssuch as morphine, pethidine, oxycodone, hydrocodone, diamorphine,tramadol, or buprenorphine. In some embodiments, a combination of two ormore analgesics is desired.

In one embodiment, the agent treating the central nervous system is amuscle relaxant or vasoconstrictor agent. In one embodiment, musclerelaxants include but are not limited to methocarbamol, baclofen,carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone,orphenadrine, amyl nitrite, pancuronium, tizanidine, clonidine, orgabapentin. In one embodiment, vasoconstrictor agents include but arenot limited to antihistamines, adrenalin dimethylarginine, caffeine,cannabis, catecholamines, decongestants, pseudoephedrinse,norepinephrines, tetrahydrozoline, or thromboxane.

In one embodiment, the agent treating the central nervous system is anantiemetic drug. In one embodiment, the antiemetic drug is a 5-HT3receptor antagonist such as dolasetron, granisetron, ondansetron, ortropisetron. In one embodiment, the antiemetic drug is a dopamineantagonist such as domperidone droperidol, haloperidol, chlorpromazine,promethazine, or metoclopramide. In one embodiment, the antiemetic drugis an antihistamine such as cyclizine, diphenhydramine, dimenhydrinate,or meclizine. In one embodiment, the antiemetic drug is a cannabinoidsuch as cannabis or marinol.

In one embodiment, the agent treating the central nervous system is asedative agent. In one embodiment, the sedative agent is anantidepressant agent such as mirtazapine or trazodone. In oneembodiment, the sedative agent is a barbiturate such as secobarbital,pentobarbital, or amobarbital. In one embodiment, the sedative agent isa benzodiazepine such as diazepam, clonazepam, alprazolam, temazepam,chlordiazepoxide, flunitrazepam, lorazepam, or clorazepate. In oneembodiment, the sedative agent is an imidazopyridines such as zolpidemor alpidem. In one embodiment, the sedative agent is aPyrazolopyrimidine such as zaleplon. In one embodiment, the sedativeagent is an antihistamine such as diphenhydramine, dimenhydrinate, ordoxylamine. In one embodiment, the sedative agent is an antipsychoticagent such as ziprasidone, risperidone, quetiapine, clozapine,prochlorperazine, perphenazine, loxapine, trifluoperazine, thiothixene,haloperidol, or fluphenazine. In one embodiment, the sedative agent isan herbal sedative such as valerian plant mandrake, or kava. In someembodiments, the sedative agent is eszopiclone, ramelteon, methaqualone,ethchlorvynol, chloral hydrate, meprobamate, glutethimide, methyprylon,gamma-hydroxybutyrate, ethyl alcohol, methyl trichloride, zopiclone, ordiethyl ether.

In one embodiment, the agent treating the central nervous system is aneurodegenerative disorder medication. In one embodiment, theneurodegenerative disorder medication is an acetylcholinesteraseinhibitor such as tacrine, donepezil, galanthamine, or rivastigmine. Inone embodiment, the neurodegenerative disorder medication is anN-methyl-D-aspartate (NMDA) antagonist such as memantine. In oneembodiment, the neurodegenerative disorder medication reduces damage tomotor neurons such as riluzole. In one embodiment, the neurodegenerativedisorder medication silences the gene that causes the progression of thedisease. In one embodiment, the agent treating the central nervoussystem is an antiepileptic drug (AED). In some embodiments,antiepileptic agents include sodium channel blockers, GABA receptoragonists, GABA reuptake inhibitors, GABA transaminase inhibitor, AEDswith a potential GABA mechanism of action, glutamate blockers, or AEDswith other mechanisms of action. In some embodiments, antiepilepticagents include but are not limited to carbamazepine, fosphenytoin,oxcarbazepine, lamotrigine, zonisamide, clobazam, clonazepam,phenobarbital, primidone, tiagabine, vigabatrin, gabapentin, valproate,felbamate, topiramate, levetiracetam, or pregabalin.

In one embodiment, the agent treating the central nervous system is ananti-addiction drug. In one embodiment, the anti-addiction is ananti-alcoholism drug such as disulfiram. In one embodiment, theanti-addiction drug is a serotonin uptake inhibitor, dopaminergicagonist, or opioid antagonist.

In one embodiment, the agent treating the central nervous system is anagent treating Alzheimer disease. In some embodiments, agents treatingAlzheimer's disease include but are not limited to a cholinesteraseinhibitor, gamma secreatse inhibitor, or a beta lowering drug.

In one embodiment, the agent treating the central nervous system is anagent treating mild cognitive impairment. In some embodiments, agentstreating mild cognitive impairment include but are not limited to anAMPA regulator.

In one embodiment, the agent treating the central nervous system is anagent treating Parkinson's disease. In some embodiments, agents treatingParkinson's disease include but are not limited to a dopaminergic drugs,amantadine, benztropine, biperiden, bromocriptine, entacapone,carbidopa/levodopa, selegiline/deprenyl, iphenhydramine, pergolide,procyclidine, selegiline, or trihexyphenidyl.

In one embodiment, the compound is administered with an agent, whichtreats Alzheimer's disease, such as cholinesterase inhibitors, gammasecreatse inhibitors, A-beta lowering drugs; or an agent, which treatsmild cognitive impairment (MCI)— such as AMPA regulators, or an agent,which treats Parkinson's Disease, such as dopaminergic drugs, or anagent, which treats Major Depression, such as SSRI's, SNRI's, forexample, duloxetine, or an agent, which treats sexual dysfunction, suchas PDE5 inhibitors.

In one embodiment, the compound is administered in combination with anagent treating the cardiovascular system. In one embodiment, the agenttreating the cardiovascular system is treating a congestive heartfailure. In one embodiment, the agent treating congestive heart failureis an angiotensin converting enzyme (ACE) inhibitor such as benazepril,captopril, cilazapril, enalapril, fosinopril, lisinopril, moexipril,perindopril, quinapril, ramipril, trandolapril, or enalaprilat. In oneembodiment, the agent treating congestive heart failure is abeta-blocker such as acebutolol, atenolol, betaxolol hydrochloride,bisoprolol fumarate, carteolol hydrochloride, carvedilol, celiprololhydrochloride, esmolol hydrochloride, labetalol hydrochloride,levobunolol, metoprolol tartrate, metipranolol, nadolol, nebivolol,oxprenolol hydrochloride, pindolol, propranolol hydrochloride, sotalolhydrochloride, or timolol maleate. In one embodiment, the agent treatingcongestive heart failure is digoxin. In one embodiment, the agenttreating congestive heart failure is a diuretic such as thiazidediuretic, loop diuretic, potassium-sparing diuretic, or a combinationthereof. In some embodiments, thiazide diuretics include but are notlimited to bendrofluazide, bendroflumethiazide, benzthiazide,chlorothiazide, chlorthalidone, cyclopenthiazide, Diucardin®, Diuril®,Enduron®, Esidrix®, Exna®, HCTZ, Hydrochlorothiazide, HydroDIURIL®,HYDROFLUMETHIAZIDE, Hydromox®, Hygroton®, indapamide, Lozol®,methyclothiazide, metolazone, Mykrox®, Naqua®, Naturetin®, Oretic®,polythiazide, quinethazone, Renese®, trichlormethiazide, xipamide, orZaroxolyn®. In some embodiments, loop diuretics include but are notlimited to furosemide/frusemide, bumetanide, or torasemide. In someembodiments, potassium-sparing diuretics include but are not limited toamiloride, triamterene, aldosterone antagonists, or spironolactone.

In one embodiment, the agent treating the cardiovascular system is ananti-arrhythmic agent. In one embodiment, the anti-arrhythmic agent is asodium channel blocker, beta-adrenergic blocker, calcium channelblocker, or an agent that prolong repolarization. In one embodiment,sodium channel blockers include but are not limited to quinidine,procainamide, disopyramide, lidocaine, tocainide, mexiletine, encainide,or flecainide. In one embodiment, beta-adrenergic blockers include butare not limited to propranolol, acebutolol, esmolol, or sotalol. In oneembodiment, agents that prolong repolarization include but are notlimited to sotalol or amiodarone. In one embodiment, calcium channelblockers include but are not limited to verapamil, diltiazem,nifedipine, or mebefradil. In one embodiment, the anti-arrhythmic agentis adenosine or digoxin.

In one embodiment, the agent treating the cardiovascular system is ananti-anginal agent. In one embodiment, the anti-anginal agent is anantiplatelet agent, adrenoceptor antagonist, calcium channel blocker, ora vasodilator. In some embodiments, the adrenoceptor antagonists andcalcium channel blockers comprise agents as described hereinabove. Inone embodiment, the antiplatelet agent is a cyclooxygenase inhibitor,ADP inhibitor, phosphodiesterase (I) inhibitor, glycoprotein IIb/IIIainhibitor, or an adenosine reuptake inhibitor. In one embodiment,cyclooxygenase inhibitors include but are not limited to acetylsalicylicacid or an acetylsalicylic acid in combination with dipyridimole. In oneembodiment, ADP inhibitors include but are not limited to clopidogrel,CS-747, or ticlopdipine. In one embodiment, phosphodiesterase IIIinhibitors include but are not limited to cilostazol. In one embodiment,glycoprotein IIb/IIIa inhibitors include but are not limited toabciximab, rheopro, eptifibatide, integrilin, tirofiban, or aggrastat.In one embodiment, adenosine reuptake inhibitors include but are notlimited to dipyridimole. In one embodiment, vasodilator agents includebut are not limited to isosorbide dinitrate, isosorbide mononitrate, ornitroglycerine. In one embodiment, cardiac glycosides such as digitalisor ouabain may be used in combination with a SARM compound.

In one embodiment, the agent treating the cardiovascular system is avasocative agent or an inotrope. In one embodiment, vasocative agents orinotropes include but are not limited to digoxin, dopamine, dobutamine,hydralazine, prazosin, carvedilol, nitroprusside, nitroglycerin,captopril, lisinopril, nifedipine, diltiazem, hydrochlorothiazide,furosemide, spironolactone, AT-1 receptor antagonists (e.g., losartan,irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan,atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and6,043,265), Dual ET/All antagonist (e.g., compounds disclosed in WO00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidaseinhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat andgemopatrilat), or nitrates.

In one embodiment, the agent treating the cardiovascular system is ananticoagulant agent. In one embodiment, the anticoagulant agent is acoumarin derivative or an unfractionated heparin. In one embodiment,coumarin derivatives include but are not limited to warfarin.

In one embodiment, the agent treating the cardiovascular system is afibrinolytic agent such as streptokinase, urokinase, alteplase,anistreplase, prourokinase, reteplase, tenecteplase, lanoteplase,staphylokinase, vampire, or alfimeprase.

In one embodiment, the agent treating the cardiovascular system is ahypercholesterolemic agent such as niacin-lovastatin, colestipol HCl,fluvastatin sodium, atorvastatin calcium, simvastatin, gemfibrozil,lovastatin, pravastatin sodium, cholestyramine, cholestyramine light,fenofibrate, colesevelam HCl, or ezetimibe.

In one embodiment, the compound of this invention is administered incombination with an agent treating the gastrointestinal system. In oneembodiment, the agent treating the gastrointestinal (GI) system isenhancing GI motility. In one embodiment, the agent enhancing GImotility is a prokinetic agent such as metoclopramide, cisapride,tegaserod, or erythromycin. In one embodiment, the agent treating the GIsystem is decreasing GI motility. In one embodiment, the agentdecreasing GI motility is an opioid such as morphine, diphenoxylate,loperamide hydrochloride, or opium.

In one embodiment, the agent treating the GI system is an adsorbent or abulking agent. In one embodiment, the adsorbent is kaolin or otherhydrated aluminum silicate clays. In one embodiment, the hydratedaluminum silicate clay is further combined with pectin. In oneembodiment, adsorbents or a bulking agents comprise bismuthsubsalicylate, methylcellulose, psyllium derivative, or calciumpolycarbophil.

In one embodiment, the agent treating the GI system is a stool softener.In one embodiment, stool softeners include but are not limited tomineral oil, docusate dioctyl sodium sulfosuccinate, dioctyl calciumsulfosuccinate, or dioctyl potassium sulfosuccinate.

In one embodiment, the agent treating the GI system is a laxative. Inone embodiment, the agent treating the GI system is a bulk forminglaxative as described hereinabove. In one embodiment, the laxative is anosmotic laxative such as lactulose, sorbitol, or polyethylene glycol. Inone embodiment, the laxative is a saline laxative such as milk ofmagnesia, magnesium citrate, sodium phosphate, docusate potassium,sorbitol, sodium phosphate-biphosphate, or visicol.

In one embodiment, the agent treating the GI system is a catharticstimulant. In one embodiment, the cathartic stimulant is ananthraquinone derivative such as cascara, aloe, senna, or rhubarb. Inone embodiment, the cathartic stimulant is phenolphthalein, castor oil,or bisacodyl.

In one embodiment, the agent treating the GI system is an emetic agent.In one embodiment, the emetic agent is ipecac or apomorphine. In oneembodiment, the agent treating the GI system is an anti-emetic agentsuch as antihistamine, anti-cholinergic agent, benzodiazepine,cannabinoid, dopamine antagonist, phenothiazine derivative, or 5-HT3antagonist such as ondansetron or granisetron.

In one embodiment, the agent treating the GI system is an antacid. Inone embodiment the antacid pharmaceutical preparation comprisesbuffering agents such as sodium bicarbonate, calcium carbonate,magnesium hydroxide, or aluminum hydroxide.

In one embodiment, the agent treating the GI system is an H2-receptorantagonist. In some embodiments, the H2-receptor antagonist iscimetidine, ranitidine, famotidine, or nizatidine.

In one embodiment, the agent treating the GI system is a proton pumpinhibitor. In some embodiments, the proton pump inhibitor is omeprazole,lansoprazole, pantoprazole, rebeprazole, or esomeprazole

In one embodiment, the agent treating the GI system is an agent treatinginflammation. In one embodiment, the agent treating inflammation is5-amino-salicylate, corticosteroid, metronidazole, ciprofloxacin,infiximab, budesonide, or anti-TNF alpha antibody.

In one embodiment, the compound of this invention is administered incombination with an agent treating a metabolic disease, disorder orcondition, which in some embodiments refers to metabolic syndrome. Insome embodiments, such agents comprise, inter alia, pancreatic lipaseinhibitors, such as for example, orlistat, cetilistat, serotonin andnorepinephrine reuptake inhibitors, such as sibutramine,insulin-sensitizers such as biguanides (metformin) or PPAR agonists,dual-acting PPAR agonists (muraglitazar, tesaglitazar, naveglitazar),PPAR-delta agonists (GW-501516), DPP-IV Inhibitors (vildagliptin,sitagliptin), alpha glucosidase inhibitors (acarbose), anti-diabeticcombinations (ActoPlusMet, AvandaMet, metformin/pioglitazone,metformin/rosiglitazone, Glucovance, etc.), glucagon-like peptide-1analogues (exenatide, liraglutide), amylin analogues (pramlintide),statins (atorvastatin, simvastatin, rosuvastatin, pravastatin,fluvastatin, lovastatin, pitavastatin), cholesterol absorptioninhibitors (ezetimibe), nicotinic acid derivatives (immediate releaseand controlled release niacins, niaslo, etc.), antidyslipidemic fixedcombinations (simvastatin/ezetimibe, lovastatin/nicotinic acid,atorvastatin/amlodipine, atorvastatin/torcetrapib, simvastatin/nicotinicacid (ER)), ACE inhibitors (ramipril, captopril, lisinopril), AT-IIreceptor antagonists (valsartan, telmisartan), cannabinoid receptorantagonists (rimonabant), cholesteryl ester transfer protein or CETPInhibitors (JTT-705, CETi-1), beta3 adrenergic agonists, PPARa ligands,or combinations thereof.

In one embodiment, the compound is administered in combination with anagent treating a dermatological disorder. In one embodiment, the agenttreating a dermatological disorder is a corticosteroid orglucocorticosteroid such as betamethasone dipropionate, clobetasol,diflorasone, amcinonide, desoximetasone, fluocinonide, aclometasone,desonide triamcinolone, fluticasone, halobetasol, mometasone, orhydrocortisone. In one embodiment, the agent treating a dermatologicaldisorder is a retinoid such as isotretinoin, acitretin, tretinoin,adapalene, tazarotene, bexarotene, alitretinoin, or beta-carotene.

In one embodiment, the agent treating a dermatological disorder isphotochemotherapy agent. In one embodiment, the photochemotherapy agentis PUVA or psoralen such as oxsoralen. In one embodiment, the agenttreating a dermatological disorder is a photodynamic agent such asporphyrin.

In one embodiment, the agent treating a dermatological disorder isdaspone, thalidomide, anti-malarial agent, antimicrobial agent, orantifungal agent. In one embodiment, the anti-malarial agent ischloroquine or hydroxychloroquine.

In one embodiment, the agent treating a dermatological disorder is anantibiotic. In one embodiment, the antibiotic is a systemic antibioticsuch as griseofulvin, ketoconazole, fluconazole, itraconazole,terbinafine, or potassium iodide. In one embodiment, the antibiotic is atopical antifungal agent. In some embodiment, topical antifungal agentsinclude but are not limited to ciclopirox, clotrimazole, econazole,ketoconazole, miconazole, naftifine, oxiconazole, terbinafine, ortolnaftate.

In one embodiment, the agent treating a dermatological disorder is anantiviral agent such as interferon alpha. In one embodiment, the agenttreating a dermatological disorder is an antiscabies agent such aspyrethrin or pyrethroid. In one embodiment, the agent treating adermatological disorder is an immunosuppressive agent such asmycophenolate motefil or 6-thioguanine. In one embodiment, the agenttreating a dermatological disorder is a topical immunosuppressive agentsuch as tacrolimus, pimecrolimus, imiquimod, 5-fluorouracil, ormechlorethamine. In one embodiment, the agent treating a dermatologicaldisorder is an antihistamine such as doxepin. In one embodiment, theagent treating a dermatological disorder is treating pigmentation suchas hydroquinone or monobenzone. In one embodiment, the agent treating adermatological disorder is a protein or a recombinant protein such asbecaplermin, etanercept, denileukin diftitox, or botulinum toxin. In oneembodiment, the agent treating a dermatological disorder is capsaicin,anthralin, benzoyl peroxide, or calcipotriene.

In one embodiment, the agent treating a dermatological disorder is akeratolytic agent. In one embodiment, the agent treating adermatological disorder is selenium sulfide. In one embodiment, theagent treating or preventing a dermatological disorder is a sunscreen.In one embodiment, the sunscreen absorbs UVB, UVA, or a combinationthereof.

In one embodiment, the agent treating a dermatological disorder may be agrowth factor such as epidermal growth factor (EGF), transforming growthfactor-α (TGF-α), platelet derived growth factor (PDGF), fibroblastgrowth factors (FGFs) including acidic fibroblast growth factor (α-FGF)and basic fibroblast growth factor (β-FGF), transforming growth factor-β(TGF-β) and insulin like growth factors (IGF-1 and IGF-2), or anycombination thereof.

In one embodiment, the compound is administered in combination with ananti-infective agent. In one embodiment, the anti-infective agent is anantibiotic agent. In one embodiment the antibiotic is a beta-lactamantibiotic. In one embodiment beta-lactam antibiotics include but arenot limited to penicillin, benzathine penicillin, benzylpenicillin,amoxicillin, procaine penicillin, dicloxacillin, amoxicillin,flucloxacillin, ampicillin, methicillin, azlocillin, carbenicillin,ticarcillin, mezlocillin, piperacillin, phenoxymethylpenicillin,co-amoxiclav, cephalosporin, cefalexin, cephalothin, cefazolin,cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceftriaxone,cefotaxime, ceftazidime, cefepime, cefpirome, imipenem, meropenem,ertapenem, faropenem, monobactam, aztreonam, or carbapenem.

In one embodiment the antibiotic is a tetracycline antibiotic. In oneembodiment tetracycline antibiotics include but are not limited totetracycline, chlortetracycline, demeclocycline, doxycycline,lymecycline, minocycline, or oxytetracycline.

In one embodiment the antibiotic is a macrolide antibiotic. In oneembodiment macrolide antibiotics include but are not limited toerythromycin, azithromycin, oxithromycin, dirithromycin, clarithromycin,josamycin, oleandomycin, kitasamycin, spiramycin, tylosin/tylocine,troleandomycin, carbomycin, cethromycin, or telithromycin.

In one embodiment the antibiotic is an aminoglycoside antibiotic. In oneembodiment, aminoglycoside antibiotics include but are not limited togentamicin, tobramycin, faropenem, imipenem, kanamycin, neomycin,ertapenem, apramycin, paromomycin sulfate, streptomycin, or amikacin.

In one embodiment the antibiotic is a quinolone antibiotic. In oneembodiment quinolone antibiotics include but are not limited tociprofloxacin, norfloxacin, lomefloxacin, enoxacin, ofloxacin,ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin,trovafloxacin, or alatrofloxacin.

In one embodiment the antibiotic is a cyclic peptide antibiotic. In oneembodiment cyclic peptide antibiotics include but are not limited tovancomycin, streptogramins, Microcin J25, Bacteriocin AS-48, RTD-1, orpolymyxins.

In one embodiment the antibiotic is a lincosamide antibiotic. In oneembodiment lincosamide antibiotics include but are not limited toclindamycin.

In one embodiment, the antibiotic is an oxazolidinone antibiotic. In oneembodiment oxazolidinone antibiotics include but are not limited tolinezolid, U-100592, DA-7867, AZD2563, or U-100766.

In one embodiment, the antibiotic is a sulfa antibiotic. In oneembodiment, sulfa antibiotics include but are not limited tosulfisoxazole.

In one embodiment, the antibiotic is an antiseptic agent. In oneembodiment, antiseptic agents include but are not limited to alcohols,chlorhexidine, chlorine, hexachlorophene, iodophors, chloroxylenol(PCMX), quaternary ammonium compounds, or triclosan.

In one embodiment, the antibiotic is an anti-tuberculosis agent. In oneembodiment an anti-tuberculosis agents include but are not limited toethambutol, rifabutin, isoniazid, rifampicin, pyrazinamide, or rifampin

In one embodiment, the antibiotic is an antifungal agent. In oneembodiment, antifungal agents include but are not limited toterbinafine, flucytosine, fluconazole, itraconazole, ketoconazole,ravuconazole, posaconazole, voriconazole, caspofungin, micafungin,v-echinocandin, amphotericin B, amphotericin B lipid complex (ABLC),amphotericin B colloidal dispersion (ABCD), liposomal amphotericin b(l-Amb), liposomal nystatin, or griseofulvin.

In one embodiment, the antibiotic is an antiprotozoal agent. In oneembodiment the antiprotozoal agent is an antimalarial agent. In oneembodiment, antimalarial agents include but are not limited tochloroquine, mefloquine, proguanil, pyrimethamine with dapsone,pyrimethamine with sulfadoxine, quinine, or primaquine. In oneembodiment, the antiprotozoal agent is an amoebicide. In one embodiment,amoebicides include but are not limited to metronidazole, timidazole, ordiloxanide furoate. In one embodiment, the antiprotozoal agent is anantigiadial agent. In one embodiment, antigiadial agents include but arenot limited to metronidazole, timidazole, or mepacrine. In oneembodiment, the antiprotozoal agent is a leishmanicide. In oneembodiment, leishmanicides include but are not limited to sodiumstibogluconate. In one embodiment, the antibiotic is an antithelminticagent.

In one embodiment, the antibiotic is an antiviral agent. In oneembodiment, antiviral agents include but are not limited to abacavir,acyclovir, amantadine, didanosine, emtricitabine, enfuvirtide,entecavir, lamivudine, nevirapine, oseltamivir, ribavirin, rimantadine,stavudine, valaciclovir, vidarabine, zalcitabine, or zidovudine. In oneembodiment, the antiviral agent is a nucleotide analog reversetranscriptase inhibitor. In one embodiment, nucleotide analog reversetranscriptase inhibitors include but are not limited totenofovir oradefovir. In one embodiment, the antiviral agent is a proteaseinhibitor. In one embodiment, protease inhibitors include but are notlimited to saquinavir, ritonavir, indinavir, nelfinavir, amprenavir,lopinavir, fosamprenavir, or tipranavir. In one embodiment, theantiviral agent is a fusion inhibitor such as enfuvirtide. In oneembodiment, a combination of antiviral or antiretroviral agents isdesired. In one embodiment, antiviral or antiretroviral agents or acombination thereof, further comprise hydroxyurea, resveratrol,grapefruit, ritonavir, leflunomide, or a combination thereof.

In one embodiment, the compound is administered in combination with anagent treating the liver. In one embodiment, the compound isadministered in combination with a statin. In some embodiment, statinsinclude but are not limited to atorvastatin, fluvastatin, lovastatin,pravastatin, simvastatin, or rosuvastatin.

In one embodiment, the compound is administered in combination with abile acid sequestrant. In some embodiment, bile acid sequestrantsinclude but are not limited to cholestyramine, colestipol, orcolesevelam.

In one embodiment, the compound is administered in combination with acholesterol absorption inhibitor. In some embodiment, cholesterolabsorption inhibitors include but are not limited to ezetimibe.

In one embodiment, the compound is administered in combination with anicotinic acid agent. In some embodiments, nicotinic acid agents includebut are not limited to niacin, niacor, or slo-niacin.

In one embodiment, the compound is administered in combination with afibrate. In some embodiments, fibrates include but are not limited togemfibrozil, or fenofibrate.

In one embodiment, the agent treating the liver is cortisone, cortisolor corticosterone. In some embodiments, the agent treating the liver iscolchicine, methotrexate, ursodeoxycholic acid, or penicillamine.

In one embodiment, the compound is administered in with an agenttreating the kidney. In one embodiment, the agent treating the kidney isa diuretic. In some embodiments, diuretics include but are not limitedto organomercurial, ethacrynic acid, frusemide, humetanide, piretanide,muzolimine, chlorothiazide and thiazide, phthalimidine, chlorthalidone,clorexolone, quinazolinone, quinethazone, metolazoneilenzenesulphonamide, mefruside, chlorobenzamide, clopamidesalicylamide,xipamide, xanthine, aminophylline, carbonic anhydrase inhibitor,acetazolamide mannitol, potassium-sparing compound, aldosteroneantagonist, spironolactone and canrenoate, pteridines, pyrazine,carboxamide-triamterene, or amiloride. In one embodiment, the agenttreating the kidney is a steroid.

In one embodiment, the agent treating the kidney is erythropoietin. Inone embodiment, erythropoietin is obtained by natural sources (e.g.,urinary erythropoietin; See U.S. Pat. No. 3,865,801), or is arecombinantly produced protein and analogs thereof, for example, asdescribed in U.S. Pat. Nos. 5,441,868, 5,547,933, 5,618,698 and5,621,080 as well as human erythropoietin analogs with increasedglycosylation and/or changes in the amino acid sequence as thosedescribed in European Patent Publication No. EP 668351 and thehyperglycosylated analogs having 1-14 sialic acid groups and changes inthe amino acid sequence described in PCT Publication No. WO 91/05867. Inone embodiment, erythropoietin-like polypeptides are administered incombination with the compounds of this invention. In some embodiments,erythropoietin-like polypeptides comprise darbepoietin (from Amgen; alsoknown as Aranesp and novel erthyropoiesis stimulating protein (NESP)).

In one embodiment, the SARM compound is administered in with an agenttreating a metabolic disease. In some embodiments, agents treating ametabolic disease include but are not limited to a vitamin, CoenzymeQ10, glucosidase alfa, sodium bicarbonate, bisphosphonate, biotin,allopurinol, levodopa, diazepam, phenobarbital, haloperidol, folic acid,antioxidants, activators of cation channels haptoglobin, or carnitine.

In one embodiment, the agent treating a metabolic disease is apancreatic lipase inhibitor such as orlistat or cetilistat, Serotonin ornorepinephrine reuptake inhibitor such as sibutramine,insulin-sensitizers such as biguanide, PPAR agonist, Dual-acting PPARagonist such as muraglitazar, tesaglitazar, or naveglitazar, PPAR-deltaagonist such as GW-501516, DPP-IV Inhibitor such as vildagliptin orsitagliptin, alpha glucosidase inhibitor such as acarbose, anti-diabeticcombination such as ActoPlusMet, AvandaMet, metformin/pioglitazone,metformin/rosiglitazone, or Glucovance, Glucagon-like peptide-1 analoguesuch as exenatide or liraglutide, Amylin analogue such as pramlintide,statin such as atorvastatin, simvastatin, rosuvastatin, pravastatin,fluvastatin, lovastatin, or pitavastatin, Cholesterol absorptioninhibitor such as ezetimibe, Nicotinic acid derivative such as niacin orniaslo, antidyslipidemic fixed combination such assimvastatin/ezetimibe, lovastatin/nicotinic acid,atorvastatin/amlodipine, or atorvastatin/torcetrapib,simvastatin/nicotinic acid, ACE inhibitor such as ramipril, captopril,or lisinopril, AT-II receptor antagonist such as valsartan ortelmisartan, cannabinoid receptor antagonist such as rimonabant,cholesteryl ester transfer protein or CETP Inhibitor such as JTT-705,CETi-1, or beta-3 adrenergic agonist.

In one embodiment, the compound is administered with an agent treating awasting disease. In some embodiments, agents treating a wasting diseaseinclude but are not limited to corticosteroids, anabolic steroids,cannabinoids, metoclopramid, cisapride, medroxyprogesterone acetate,megestrol acetate, cyproheptadine, hydrazine sulfate, pentoxifylline,thalidomide, anticytokine antibodies, cytokine inhibitors,eicosapentaenoic acid, indomethacin, ibuprofen, melatonin, insulin,growth hormone, clenbuterol, porcine pancreas extract, IGF-1, IGF-1analogue and secretagogue, myostatin analogue, proteasome inhibitor,testosterone, oxandrolone, enbrel, melanocortin 4 receptor agonist, or acombination thereof.

In one embodiment, the agent treating a wasting disease is a ghrelinreceptor ligand, growth hormone analogue, or a secretagogue. In someembodiments, ghrelin receptor ligands, growth hormone analogues, orsecretagogues include but are not limited to pralmorelin, examorelin,tabimorelin, capimorelin, capromorelin, ipamorelin, EP-01572, EP-1572,or JMV-1843.

In one embodiment, growth promoting agents such as but not limited toTRH, diethylstilbesterol, theophylline, enkephalins, E seriesprostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, e.g.,zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g.,sulbenox or peptides disclosed in U.S. Pat. No. 4,411,890 are utilizedas agents treating a wasting disease.

In other embodiments, agents treating a wasting disease may comprisegrowth hormone secretagogues such as GHRP-6, GHRP-1 (as described inU.S. Pat. No. 4,411,890 and publications WO 89/07110 and WO 89/07111),GHRP-2 (as described in WO 93/04081), NN703 (Novo Nordisk), LY444711(Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or, in otherembodiments, with growth hormone releasing factor and its analogs orgrowth hormone and its analogs, or with alpha-adrenergic agonists, suchas clonidine or serotinin 5-HTD agonists, such as sumatriptan, or agentswhich inhibit somatostatin or its release, such as physostigmine andpyridostigmine. In some embodiments, agents treating a wasting diseasemay comprise parathyroid hormone, PTH(1-34) or bisphosphonates, such asMK-217 (alendronate). In other embodiments, agents treating wastingdisease may further comprise estrogen, a selective estrogen receptormodulator, such as tamoxifene or raloxifene, or other androgen receptormodulators, such as those disclosed in Edwards, J. P. et. al., Bio. Med.Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et. al., J. Med.Chem., 42, 210-212 (1999). In some embodiments, agents treating awasting disease may further comprise a progesterone receptor agonists(“PRA”), such as levonorgestrel, medroxyprogesterone acetate (MPA). Insome embodiments, agents treating a wasting disease may includenutritional supplements, such as those described in U.S. Pat. No.5,179,080, which, in other embodiments are in combination with wheyprotein or casein, amino acids (such as leucine, branched amino acidsand hydroxymethylbutyrate), triglycerides, vitamins (e.g., A, B6, B 12,folate, C, D and E), minerals (e.g., selenium, magnesium, zinc,chromium, calcium and potassium), camitine, lipoic acid, creatinine,B-hyroxy-B-methylbutyriate (Juven) and coenzyme Q. In one embodiment,agents treating a wasting disease may further comprise antiresorptiveagents, vitamin D analogues, elemental calcium and calcium supplements,cathepsin K inhibitors, MMP inhibitors, vitronectin receptorantagonists, Src SH2 antagonists, vacular-H+-ATPase inhibitors,ipriflavone, fluoride, tibolone, prostanoids, 17-beta hydroxysteroiddehydrogenase inhibitors and Src kinase inhibitors.

In one embodiment, the compound is administered in with an agenttreating the endocrine system. In some embodiments, agents treating theendocrine system include but are not limited to radioactive iodine,antithyroid agent, thyroid hormone supplement, growth hormone,cabergoline, bromocriptine, thyroxine, gonadotropin, glucocorticoid,glucocorticoid analogue, corticotrophin, metyrapone, aminoglutethimide,mitotane, ketoconazole, mifepristone, dexamethasone somatostatinanalogue, gonadotropin-releasing hormone analogue, leuprolide,goserelin, antidiuretic hormone, antidiuretic hormone analogue,oxytocin, calcium supplement, vitamin D, or a combination thereof.

In one embodiment, the agent treating the endocrine system is a5-alpha-reductase inhibitor. In some embodiments, 5-alpha-reductaseinhibitors include but are not limited to finasteride, dutasteride, orizonsteride.

In one embodiment, the agent treating the endocrine system is a SARMcompound. In some embodiments, SARMs include but are not limited toRU-58642, RU-56279, WS9761 A and B, RU-59063, RU-58841, bexlosteride,LG-2293, L-245976, LG-121071, LG-121091, LG-121104, LGD-2226, LGD-2941,YM-92088, YM-175735, LGD-1331, BMS-357597, BMS-391197, S-40503,BMS-482404, EM-4283, EM-4977, BMS-564929, BMS-391197, BMS-434588,BMS-487745, BMS-501949, SA-766, YM-92088, YM-580, LG-123303, LG-123129,PMCol, YM-175735, BMS-591305, BMS-591309, BMS-665139, BMS-665539,CE-590, 116BG33, 154BG31, arcarine, or ACP-105.

In one embodiment, the additional agent treating the endocrine system isa SERM compound. In some embodiments, SERMs include but are not limitedto tamoxifene, 4-hydroxytamoxifene, idoxifene, toremifene, ospemifene,droloxifene, raloxifene, arzoxifene, bazedoxifene, PPT(1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN, lasofoxifene,pipendoxifene, EM-800, EM-652, nafoxidine, zindoxifene, tesmilifene,miproxifene phosphate, RU 58,688, EM 139, ICI 164,384, ICI 182,780,clomiphene, MER-25, diethylstibestrol, coumestrol, genistein, GW5638,LY353581, zuclomiphene, enclomiphene, delmadinone acetate, DPPE,(N,N-diethyl-2-{4-(phenylmethyl)-phenoxy}ethanamine), TSE-424, WAY-070,WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, WAY-244,ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380,BE-381, WAY-358, [18F]FEDNP, LSN-500307, AA-102, Ban zhi lian, CT-101,CT-102, or VG-101.

In one embodiment, the agent treating the endocrine system is agonadotropin-releasing hormone agonist or antagonist. In someembodiments, gonadotropin-releasing hormone agonists or antagonistsinclude but are not limited to leuprolide, goserelin, triptorelin,alfaprostol, histrelin, detirelix, ganirelix, antide iturelix,cetrorelix, ramorelix, ganirelix, antarelix, teverelix, abarelix,ozarelix, sufugolix, prazarelix, degarelix, NBI-56418, TAK-810, oracyline.

In one embodiment, the agent treating the endocrine system is aluteinizing hormone agonist or antagonist. In some embodiments,luteinizing hormone agonists or antagonists include but are not limitedto letrozole, anastrazole, atamestane, fadrozole, minamestane,exemestane, plomestane, liarozole, NKS-01, vorozole, YM-511, finrozole,4-hydroxyandrostenedione, aminogluethimide, or rogletimide. In oneembodiment, the agent treating the endocrine system is a folliclestimulating hormone agonist or antagonist. In one embodiment, the agenttreating the endocrine system is a luteinizing hormone releasing hormone(LHRH) or a LHRH analog.

In one embodiment, the agent treating the endocrine system is asteroidal or nonsteroidal glucocorticoid receptor ligand. In someembodiments, nonsteroidal glucocorticoid receptor ligands include butare not limited to ZK-216348, ZK-243149, ZK-243185, LGD-5552,mifepristone, RPR-106541, ORG-34517, GW-215864X, Sesquicillin,CP-472555, CP-394531, A-222977, AL-438, A-216054, A-276575, CP-394531,CP-409069, or UGR-07.

In one embodiment, the agent treating the endocrine system is asteroidal or non-steroidal progesterone receptor ligand. In oneembodiment, the agent treating the endocrine system is a steroidal ornonsteroidal androgen receptor antagonist. In some embodiments,steroidal or nonsteroidal androgen receptor antagonists include but arenot limited to flutamide, hydroxyflutamide, bicalutamide, nilutamide, orhydroxysteroid dehydrogenase inhibitor.

In one embodiment, the agent treating the endocrine system is aperoxisome proliferator-activated receptor ligand. In some embodiments,peroxisome proliferator-activated receptor ligands include but are notlimited to bezafibrate, fenofibrate, gemfibrozil, darglitazone,pioglitazone, rosiglitazone, isaglitazone, rivoglitazone, netoglitazone,naveglitazar, farglitazar, tesaglitazar, ragaglitazar, oxeglitazar, orPN-2034.

In one embodiment, an agent treating the endocrine system is a humangrowth hormone. In some embodiments, human growth hormones include butare not limited to somatotropin or analogues.

In one embodiment, the agent treating the endocrine system is a ghrelin.In some embodiments, ghrelins include but are not limited to humanghrelin, CYT-009-GhrQb, L-692429, GHRP-6, SK&F-110679, or U-75799E.

In one embodiment, the agent treating the endocrine system is a leptin.In some embodiments, leptins include but are not limited to metreleptinor pegylated leptin. In one embodiment, an agent treating the endocrinesystem is a leptin receptor agonist. In some embodiments, leptinreceptor agonists include but are not limited to LEP(116-130), OB3,[D-Leu4]-OB3, rAAV-leptin, AAV-hOB, or rAAVhOB.

In one embodiment, the SARM compound is administered with an inhibitorof an enzyme involved in the androgen biosynthetic pathway. In someembodiments, inhibitors of enzymes involved in the androgen biosyntheticpathway include but are not limited to 17-ketoreductase inhibitor,3-DH4,6-isomerase inhibitor, 3-DH4,5-isomerase inhibitor, 17,20desmolase inhibitor, p450c17 inhibitor, p450ssc inhibitor, or17,20-lyase inhibitor.

In one embodiment, the compound of this invention is administered withan agent treating osteoporosis. In some embodiments, osteoporosis isinduced by alcohol and/or smoking. In some embodiments, agents treatingosteoporosis include but are not limited to SERMs, calcitonin, vitaminD, vitamin D derivatives, vitamin D receptor ligand, vitamin D receptorligand analogue, estrogen, estrogen derivative, conjugated estrogen,antiestrogen, progestin, synthetic estrogen, synthetic progestin, RANKligand monoclonal antibody, integrin receptor antagonist, osteoclastvacuolar ATPase inhibitor, antagonist of VEGF binding to osteoclastreceptors, calcium receptor antagonist, parathyroid hormone, parathyroidhormone analogue, parathyroid hormone-related peptide, cathepsin Kinhibitor, strontium ranelate, tibolone, HCT-1026, PSK3471, galliummaltolate, nutropin AQ, prostaglandin, p38 protein kinase inhibitor,bone morphogenetic protein (BMP), inhibitor of BMP antagonism, HMG-CoAreductase inhibitor, vitamin K, vitamin K derivative, ipriflavone,fluoride salts, dietary calcium supplement, or osteoprotegerin.

In one embodiment, the agent treating osteoporosis is a calcitonin. Insome embodiments, calcitonins include but are not limited to salmon,elcatonin, SUN-8577, or TJN-135.

In one embodiment, the agent treating osteoporosis is a vitamin Dreceptor ligand or analogue. In some embodiments, vitamin D receptorligands or analogues include but are not limited to calcitriol,topitriol, ZK-150123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299,Ro-65-2299, or DP-035.

In one embodiment, the compound of this invention is administered withan agent treating pharmacotherapy induced hypogonadal and/or osteopenicand/or sarcopenic state. In some embodiments, agents treatingpharmacotherapy induced hypogonadal and/or osteopenic and/or sarcopenicstates include but are not limited to opioids, narcotics, opiates,opioids, methadone, kadian, D2 dopamine receptor antagonist, zotepine,haloperidol, amisulpride, risperidone, anti-epileptic agent, valproicacid, carbamazepine, oxcarbamazepine, chemotherapeutic agent,methotrexate, cyclophosphamide, ifosfamide, adriamycin, doxorubicin,glucocorticoids, cyclosporine, L-thyroxine, SERMs, AI, fulvestrant,gonadotropin-releasing hormone agent, androgen depravation agent,prolactinemia-inducing agent, serotonergic antidepressant, selectiveserotonin reuptake inhibitor, monoamine oxidase inhibitor, tricyclicantidepressant, antihypertensive agents, methyldopa, reserpine,clonidine, verapamil, antidopaminergic agent, anti-emetic agent,metoclopramide, H2 receptor antagonist, cimetidine, ranitidine,estrogen, or amphetamine.

In one embodiment, the compound of this invention is administered with avitamin. In some embodiments, vitamins include but are not limited tovitamin D, vitamin E, vitamin K, vitamin B, vitamin C, or a combinationthereof.

In one embodiment, the compound of this invention is administered with abehavior-modulating agent. In some embodiments, behavior-modulatingagents include but are not limited to an anti-anxiety agent,anti-psychotic agent, anti-depressant, beta-blocker, beta-2 agonist,anticholinergic bronchodilator, theophylline, aminophylline, nedocromilsodium, sodium cromoglycate, leukotriene receptor antagonist,corticosteroid, expectorant, mucolytic agent, antihistamine,pseudoephedrine, methylphenidate, amphetamine, buspirone,benzodiazepine, dextroamphetamine, tricyclic antidepressant, serotoninreuptake inhibitor, phenothiazines, benztropine, bupropion, propranolol,lithium, venlafaxine, haloperidol, buspirone, or a neuraminidaseinhibitor.

In one embodiment, the behavior-modulating agent is a benzodiazepine. Inone embodiment, benzodiazepines comprise alprazolam, chlordiazepoxide,diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam.

In one embodiment, the behavior-modulating agent is a phenothiazine. Inone embodiment, phenothiazines comprise fluphenazine, perphenazine,thioridazine, or trifluoperazine.

In one embodiment, the behavior-modulating agent is a tricyclicantidepressant or a serotonin reuptake inhibitor. In one embodiment,tricyclic antidepressants or serotonin reuptake inhibitors comprisephenothiazine, protriptyline, fluoxetine, paroxetine, or sertraline.

In one embodiment, the compound of this invention is administered withan agent treating a connective tissue. In some embodiments, agentstreating a connective tissue include but are not limited to ananti-malaria agent, a cytotoxic agent, a steroid, corticosteroid, lupusmedication, imuran, cytoxan, anti-rheumatic agent, corticosteroid,nifedipine, aspirin, colchicine, captopril, penicillamine, azathioprine,methotrexate, cyclophosphamide, prednisone, nicardipine, or anon-steroidal anti-inflammatory agent.

In one embodiment, the compound of this invention is administered withan agent treating an ophthalmic disease. In some embodiments, agentstreating an ophthalmic disease include but are not limited to betagan,betimol, timoptic, betoptic, betoptic, ocupress, optipranolol, xalatan,alphagan, azopt, trusopt, cospot, pilocar, pilagan, propine, opticrom,acular, livostin, alomide, emadine, patanol, alrex, poly-pred, pred-g,dexacidin, erythromycin, maxitrol, tobradex, blephamide, FML, ocufen,voltaren, profenal, pred forte, econpred plus, eflone, flarex, inflamaseforte, betadine, gramicidin, prednisolone, betaxolol, humorsol,proparacaine, betoptic, hylartin, inflamase mild, lotemax, flurbiprofen,chloramphenicol, methazolamide, timolol, ciloxan, terramycin,ciprofloxacin, miostat, triamcinolone, miconazole, tobramycin,physostimine, gentamicin, pilocarpine, bacitracin, goniosol, polymyxin,oxytetracycline, viroptic, vexol, suprofen, celluvisc, polytrim,illotycin, ciloxan, ocuflox, brinzolamide, cefazolin, tobrex,latanoprost, indocycanine, trifluridine, phenylephrine, demecarium,neomycin, tropicamide, dexamethasone, neptazane, dipivefrin, ocuflox,vidarabine, dorzolamide, ofloxacin, epinephrine, acyclovir, carbonicanhydrase inhibitor, antihistamine vitamin A, vitamin C, vitamin E,zinc, copper, atropine, or garamycin.

In one embodiment, the compound of this invention is administered inwith a gene therapy agent. In some embodiments, gene therapy agentsinclude but are not limited to an antisense agent, or a replacementgene.

In some embodiments, any of the compositions of this invention willcomprise a compound of this invention, in any form or embodiment asdescribed herein. In some embodiments, any of the compositions of thisinvention will consist of a compound of this invention, in any form orembodiment as described herein. In some embodiments, of the compositionsof this invention will consist essentially of a compound of thisinvention, in any form or embodiment as described herein. In someembodiments, the term “comprise” refers to the inclusion of theindicated active agent, such as the compound of this invention, as wellas inclusion of other active agents, and pharmaceutically acceptablecarriers, excipients, emollients, stabilizers, etc., as are known in thepharmaceutical industry. In some embodiments, the term “consistingessentially of” refers to a composition, whose only active ingredient isthe indicated active ingredient, however, other compounds may beincluded which are for stabilizing, preserving, etc. the formulation,but are not involved directly in the therapeutic effect of the indicatedactive ingredient. In some embodiments, the term “consisting essentiallyof” may refer to components which facilitate the release of the activeingredient. In some embodiments, the term “consisting” refers to acomposition, which contains the active ingredient and a pharmaceuticallyacceptable carrier or excipient.

In one embodiment, the present invention provides combined preparations.In one embodiment, the term “a combined preparation” defines especiallya “kit of parts” in the sense that the combination partners as definedabove can be dosed independently or by use of different fixedcombinations with distinguished amounts of the combination partnersi.e., simultaneously, concurrently, separately or sequentially. In someembodiments, the parts of the kit of parts can then, e.g., beadministered simultaneously or chronologically staggered, that is atdifferent time points and with equal or different time intervals for anypart of the kit of parts. The ratio of the total amounts of thecombination partners, in some embodiments, can be administered in thecombined preparation. In one embodiment, the combined preparation can bevaried, e.g., in order to cope with the needs of a patient subpopulationto be treated or the needs of the single patient which different needscan be due to a particular disease, severity of a disease, age, sex, orbody weight as can be readily made by a person skilled in the art.

It is to be understood that this invention is directed to compositionsand combined therapies as described herein, for any disease, disorder orcondition, as appropriate, as will be appreciated by one skilled in theart. Certain applications of such compositions and combined therapieshave been described hereinabove, for specific diseases, disorders andconditions, representing embodiments of this invention, and methods oftreating such diseases, disorders and conditions in a subject byadministering a compound as herein described, alone or as part of thecombined therapy or using the compositions of this invention representadditional embodiments of this invention.

Biological Activity of Selective Androgen Modulator Compounds

The compounds of this invention may be useful, in some embodiments, fororal testosterone replacement therapy. In other embodiments,appropriately substituted compounds are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with ADAM, such as fatigue,depression, decreased libido, sexual dysfunction, erectile dysfunction,hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia,benign prostate hyperplasia, and alterations in mood and cognition; c)treatment of conditions associated with ADIF, such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of chronic muscularwasting; e) treatment of prostate cancer, imaging of prostate cancer;decreasing the incidence of, halting or causing a regression of prostatecancer; f) treatment of diabetes type I; g) treatment of diabetes typeII; h) suppressing or inhibiting or reducing the incidence of diabetesi) treatment of glucose intolerance; j) treatment of hyperinsulinemia;k) treatment of insulin resistance l) treatment of diabetic nephropathy;m) treatment of diabetic neuropathy; n) treatment of diabeticretinopathy; o) treatment of fatty liver condition; p) treatment ofcachexia; q) oral androgen replacement and/or other clinical therapeuticand/or diagnostic areas, including any embodiment of what is encompassedby the term “treating” as described herein.

In some embodiments, the compounds of this invention possess in vivotissue selective androgenic and anabolic activity, which is accordinglyutilized for particular applications, as will be appreciated by oneskilled in the art.

In one embodiment, this invention provides: a) a method of treating asubject having a muscle wasting disorder; b) a method of treating asubject suffering from malnutrition; c) a method of treating abone-related disorder in a subject; d) a method of increasing a bonemass in a subject; e) a method of improving the lipid profile in asubject; f) a method of treating atherosclerosis and its associateddiseases; g) a method of improving dexterity and movement in a subject;h) a method of treating a subject having dwarfism; i) a method oftreating a subject having dysmenorrhea; j) a method of treating asubject having dysparunia; k) a method of treating a subject havingdysspermtogenic sterility; comprising the step of administering to saidsubject a compound of this invention and/or an analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, impurity or crystal ofsaid compound, or any combination thereof.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications andtreating diseases in which the improvement of cognition, reduction ortreatment of depression, or other neuroprotective effects are desired.

In one embodiment, “Cognition” refers to the process of knowing,specifically the process of being aware, knowing, thinking, learning andjudging. Cognition is related to the fields of psychology, linguistics,computer science, neuroscience, mathematics, ethology and philosophy. Inone embodiment, “mood” refers to a temper or state of the mind Ascontemplated herein, alterations mean any change for the positive ornegative, in cognition and/or mood.

In one embodiment, “depression” refers to an illness that involves thebody, mood and thoughts that affects the way a person eats, sleeps andthe way one feels about oneself, and thinks about things. The signs andsymptoms of depression include loss of interest in activities, loss ofappetite or overeating, loss of emotional expression, an empty mood,feelings of hopelessness, pessimism, guilt or helplessness, socialwithdrawal, fatigue, sleep disturbances, trouble concentrating,remembering, or making decisions, restlessness, irritability, headaches,digestive disorders or chronic pain.

In one embodiment, the methods of this invention are useful a subject,which is a human. In another embodiment, the subject is a mammal. Inanother embodiment the subject is an animal. In another embodiment thesubject is an invertebrate. In another embodiment the subject is avertebrate.

In one embodiment, the subject is male. In another embodiment, thesubject is female. In some embodiments, while the methods as describedherein may be useful for treating either males or females, females mayrespond more advantageously to administration of certain compounds, forcertain methods, as described and exemplified herein.

In some embodiments, while the methods as described herein may be usefulfor treating either males or females, males may respond moreadvantageously to administration of certain compounds, for certainmethods, as described herein.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in ortreating hair loss, alopecia, androgenic alopecia, alopecia areata,alopecia secondary to chemotherapy, alopecia secondary to radiationtherapy, alopecia induced by scarring or alopecia induced by stress. Inone embodiment, “hair loss”, or “alopecia”, refers to baldness as in thevery common type of male-pattern baldness. Baldness typically beginswith patch hair loss on the scalp and sometimes progresses to completebaldness and even loss of body hair. Hair loss affects both males andfemales.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in, ortreating diseases or conditions associated with a subject having anemia.In one embodiment, “anemia” refers to the condition of having less thanthe normal number of red blood cells or less than the normal quantity ofhemoglobin in the blood, reduced hematocrit or reduced mean corpuscularvolume, or reduced corpuscular size. The oxygen-carrying capacity of theblood is decreased in anemia. In some embodiments, treating anemia mayalso refer herein to treating underlying factors resulting in anemia,such as for example: a) hemorrhage (bleeding); b) hemolysis (excessivedestruction of red blood cells); c) underproduction of red blood cells;and d) not enough normal hemoglobin. In some embodiments, treatinganemia in this invention refers to treating any form thereof, includingaplastic anemia, benzene poisoning, Fanconi anemia, hemolytic disease ofthe newborn, hereditary spherocytosis, iron deficiency anemia,osteoporosis, pernicious anemia, aplastic anemia, hemolytic anemia,sickle cell anemia, renal anemia, thalassemia, myelodysplastic syndrome,and a variety of bone marrow diseases.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in and/ortreating diseases and/or conditions associated with problems with asubject's libido, or erectile dysfunction in a subject. In oneembodiment, “libido”, may refer to sexual desire.

In one embodiment, the term “erectile” refers to the ability to be erector upright. An erectile tissue is a tissue, which is capable of beinggreatly dilated and made rigid by the distension of the numerous bloodvessels, which it contains.

In another embodiment of the present invention, a method is provided forhormonal therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes contacting an androgenreceptor of a patient with a compound and/or a non steroidal agonist ofthe present invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, hydrate, N-oxide or any combination thereof, in anamount effective to bind the compound to the androgen receptor andeffect a change in an androgen-dependent condition.

In one embodiment of this invention, a method is provided for hormonereplacement therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes administering a compound asherein described and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, hydrate, N-oxide or any combination thereof, to asubject, in an amount sufficient to effect a change in ahormone-dependent condition in the subject.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, comprising the methods of thepresent invention include those conditions which are associated withaging, hypogonadism, sarcopenia, diminished erythropoiesis,osteoporosis, and any other conditions dependent upon low androgen(e.g., testosterone) or estrogen levels.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, and comprising a method of theinvention, may comprise conditions characterized by elevated androgen orestrogen levels, including hirsutism, infertility, polycystic ovariansyndrome, endometrial carcinoma, breast cancer, male pattern baldness,prostate cancer, testicular cancer, and others, as will be known to oneskilled in the art. For such conditions, the subject may be administereda compound as herein described, alone or in combination with anothertherapeutic agent, as will be appreciated by one skilled in the art.

In one embodiment, this invention provides methods for the treatment ofa cancer in a subject, reduction of incidence or severity orpathogenesis of a cancer in a subject, delaying progression, prolongingremission or delaying onset of cancer in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, hydrate,N-oxide or any combination thereof. In some embodiments, such cancersare hormone-dependent or androgen receptor dependent tumors (malignantor benign) associated with reproductive tissue in males or females, suchas cancer of the prostate, ovary, breast, uterus, testicle, or others.

In some embodiments, this invention provides methods for the treatmentof a precancerous precursor or lesion in a subject, reduction ofincidence of precancerous precursors or lesions in a subject, comprisingthe step of administering to the subject a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,hydrate, N-oxide or any combination thereof. In some embodiments, suchprecancerous precursors are androgen receptor dependent tumors found inhormone-responsive tissue or are associated with reproductive tissue inmales or females, such as in the prostate, ovary, breast, uterus,testicle, or others. In some embodiments, such precancerous precursorscomprise any local intraepithelial neoplasia, for example, of theprostate, the cervix, etc. In some embodiments, such methods are usefulin treating neoplasia or pre-neoplasia, dysplasia or hyperplasia in atissue, such as in reproductive tissue in males or females.

In one embodiment, this invention provides compounds, compositionsand/or methods of use thereof in treating benign prostate hyperplasia(BPH). “BPH (benign prostate hyperplasia)” is a nonmalignant enlargementof the prostate gland, and is the most common non-malignantproliferative abnormality found in any internal organ and the majorcause of morbidity in the adult male. BPH occurs in over 75% of men over50 years of age, reaching 88% prevalence by the ninth decade. BPHfrequently results in a gradual squeezing of the portion of the urethrawhich traverses the prostate (prostatic urethra). This causes patientsto experience a frequent urge to urinate because of incomplete emptyingof the bladder and urgency of urination. The obstruction of urinary flowcan also lead to a general lack of control over urination, includingdifficulty initiating urination when desired, as well as difficulty inpreventing urinary flow because of the inability to empty urine from thebladder, a condition known as overflow urinary incontinence, which canlead to urinary obstruction and to urinary failure.

In another embodiment, the invention provides a method of treating,delaying onset, reducing the incidence of or reducing the severity ofprostate cancer in a subject with prostate cancer comprisingadministering a compound of formula (I)-(XI), to said subject.

In some embodiments ER-β agonists are useful treating, delaying onset,reducing the incidence of or reducing the severity of prostate cancer ina subject. In another embodiment, ER-β agonist of this invention iscompound 3a, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3d, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3e, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3l,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3g, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 3j, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3i, listed inTable 1, or any combination thereof. In another embodiment, ER-β agonistof this invention is compound 4a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 4h, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 4u, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10o, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10f, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10l, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10w, listed inTable 1, or any combination thereof.

In one embodiment, the method comprises administering prodrug, ester,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,hydrate or any combination thereof of the compound of formula (I)-(XI)to the subject. In another embodiment, the compound is 3a, 3d, 3e, 3l,3g, 3j, 3i, 4a, 4d, 4u, 10o, 10d, 10f, 10l, or 10w.

In some embodiments, the method comprises administering a compositioncomprising a compound of formula (I)-(XI) or its prodrug, ester, analog,isomer, metabolite, derivative, pharmaceutically acceptable salt,pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrateor any combination thereof, to the subject. In another embodiment, thecompound is 3a, 3d, 3e, 3l, 3g, 3j, 3i, 4a, 4d, 4u, 10o, 10d, 10f, 10l,or 10w.

In another embodiment, the invention provides a method of reducing therisk of developing prostate cancer in a mammalian subject comprisingadministering a compound of formula (I)-(XI) or its prodrug, analog,isomer, metabolite, derivative, pharmaceutically acceptable salt,pharmaceutical product, ester, polymorph, crystal, impurity, N-oxide,hydrate or any combination thereof to the subject. In some embodimentsER-β agonists are useful in reducing the risk of developing prostatecancer in a mammalian subject. In another embodiment, ER-β agonist ofthis invention is compound 3a, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3d, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3e,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3l, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 3g, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3j, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 3i, listed in Table 1, or any combination thereof. In anotherembodiment, ER-β agonist of this invention is compound 4a, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 4h, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 4u, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 10o, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 10d,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 10f, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 10l, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10w, listed inTable 1, or any combination thereof.

In another embodiment, the invention provides a method of treating,delaying onset, reducing the incidence of or reducing the numberprecancerous precursors of prostate adenocarcinoma lesions in amammalian subject comprising administering a compound of formula(I)-(XI) or its prodrug, ester, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof to thesubject. In another embodiment, the precancerous precursor of prostateadenocarcinoma is prostate intraepithelial neoplasia (PIN). In someembodiments ER-β agonists are useful in treating, delaying onset,reducing the incidence of or reducing the number precancerous precursorsof prostate adenocarcinoma lesions in a mammalian subject. In anotherembodiment, ER-β agonist of this invention is compound 3a, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 3d, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3e, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3l, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3g,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3j, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 3i, listed in Table 1, or any combinationthereof. In another embodiment, ER-β agonist of this invention iscompound 4a, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 4h, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 4u, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 10o,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 10d, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 10f, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10l, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10w, listed in Table 1, or any combination thereof.

In another embodiment, the invention provides a method of treating,preventing, suppressing, inhibiting, or reducing the incidence oftesticular cancer in a mammalian subject comprising administering acompound of formula (I)-(XI) or its prodrug, ester, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, hydrate or anycombination thereof to the subject. In another embodiment, the inventionprovides a method of treating, preventing, suppressing, inhibiting, orreducing the incidence of a urogenital disorder, disease or condition ina mammalian subject comprising administering a compound of formula(I)-(XI) or its prodrug, ester, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof to thesubject. In some embodiments ER-β agonists are useful in treating,preventing, suppressing, inhibiting, or reducing the incidence oftesticular cancer in a mammalian subject. In another embodiment, ER-βagonist of this invention is compound 3a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 3e, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3l, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3g, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3j,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3i, listed in Table 1, or any combination thereof. Inanother embodiment, ER-β agonist of this invention is compound 4a,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 4h, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 4u, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10o, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10d, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10f, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10l, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10w, listed in Table 1, or any combination thereof.

In one embodiment, according to these aspects of the invention, themethods are appropriate for treating, suppressing, inhibiting, reducingthe risk of developing latent prostate cancer.

It is to be understood that any of the methods may be effected via theadministration of a composition comprising the indicated compound orcompounds, and represents embodiments of this invention.

In some embodiments, this invention provides compounds, compositions andmethods of use thereof in the treatment of a cancer, or a precancerousprecursor thereof or a hyperplasia. In some embodiments, such neoplasia,preneoplasias or hyperplasias may be of any cell type, such as, forexample, an epithelial cell. In some embodiments, such cancers,precancerous lesions or hyperplastic lesions, which may be positivelyaffected by the NRBAs or compositions of this invention may comprisethose of thyroid, liver, bladder, kidney, head and neck tissue,pancreas, urogenital tract, GI tract, nervous and supporting tissue, orcombinations thereof. In some embodiments, compounds and compositions ofthis invention are beneficial when administered at an early,preneoplastic stage. In some embodiments, the compounds and compositionsof this invention are beneficial when administered at latter stages ofdisease, for example, in the prevention of metastasis from a primaryfocus. In some embodiments, the compounds, compositions and methods ofthis invention are beneficial when administered at any, or at multiplestages of carcinogenesis in a subject, or pre-cancerous stages orcombinations thereof.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofa carcinoma in a subject, comprising administering a compound of formula(I)-(XI), which in some embodiments is a SERM, or its prodrug, analog,isomer, metabolite, derivative, pharmaceutically acceptable salt,pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester,hydrate or any combination thereof, to the subject.

In another embodiment of the present invention, the method for treatingbenign prostate hyperplasia (BPH) in a subject, comprises the step ofadministering to the subject a compound as herein described and/or itsanalog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, hydrate,N-oxide or any combination thereof, in an amount effective to treat BPHin the subject.

In some embodiments, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, or reducing pathogenesis of cachexia and/or cachexia associated withcancer in a subject. In another embodiment, the cancer compriseadrenocortical carcinoma, anal cancer, bladder cancer, brain tumor,brain stem glioma, brain tumor, cerebellar astrocytoma, cerebralastrocytoma, ependymoma, medulloblastoma, supratentorial primitiveneuroectodermal, pineal tumors, hypothalamic glioma, breast cancer,carcinoid tumor, carcinoma, cervical cancer, colon cancer, endometrialcancer, esophageal cancer, extrahepatic bile duct cancer, ewings familyof tumors (Pnet), extracranial germ cell tumor, eye cancer, intraocularmelanoma, gallbladder cancer, gastric cancer, germ cell tumor,extragonadal, gestational trophoblastic tumor, head and neck cancer,hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia,acute lymphoblastic, leukemia, oral cavity cancer, liver cancer, lungcancer, non small cell lung cancer, small cell, lymphoma, AIDS-relatedlymphoma, central nervous system (primary), lymphoma, cutaneous T-cell,lymphoma, Hodgkin's disease, non-Hodgkin's disease, malignantmesothelioma, melanoma, Merkel cell carcinoma, metasatic squamouscarcinoma, multiple myeloma, plasma cell neoplasms, mycosis fungoides,myelodysplastic syndrome, myeloproliferative disorders, nasopharyngealcancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarianepithelial cancer, ovarian germ cell tumor, ovarian low malignantpotential tumor, pancreatic cancer, exocrine, pancreatic cancer, isletcell carcinoma, paranasal sinus and nasal cavity cancer, parathyroidcancer, penile cancer, pheochromocytoma cancer, pituitary cancer, plasmacell neoplasm, prostate cancer, rhabdomyosarcoma, rectal cancer, renalcell cancer, salivary gland cancer, Sezary syndrome, skin cancer,cutaneous T-cell lymphoma, skin cancer, Kaposi's sarcoma, skin cancer,melanoma, small intestine cancer, soft tissue sarcoma, soft tissuesarcoma, testicular cancer, thymoma, malignant, thyroid cancer, urethralcancer, uterine cancer, sarcoma, unusual cancer of childhood, vaginalcancer, vulvar cancer, Wilms' tumor, or any combination thereof.

In another embodiment, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, delaying the onset of lung cancer.

In another embodiment, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, delaying the onset of non small cell lung cancer.

Colon cancer is the second most frequently diagnosed malignancy in theUnited States, as well as the second most common cause of cancer death.Cholesterol-rich diets have had a significant epidemiologicalassociation with cancers of the colon, which in turn may be influencedby the administration of compounds which modulate nuclear hormonebinding agents, in particular, compounds which modulate receptorsbinding components of the steroidogenic pathway, in particular SERMs, asdescribed herein.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofcolon cancer in a subject, comprising administering a compound offormula (I)-(XI), which in some embodiments is a SERM, or its prodrug,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,ester, hydrate or any combination thereof, to the subject. In someembodiments ER-β agonists are useful in treating, preventing therecurrence, inhibiting, reducing the incidence of, delaying onset,reducing the recurrence of, or reducing the severity of colon cancer ina subject. In another embodiment, ER-β agonist of this invention iscompound 3a, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3d, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3e, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3l,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3g, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 3j, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3i, listed inTable 1, or any combination thereof. In another embodiment, ER-β agonistof this invention is compound 4a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 4h, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 4u, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10o, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10f, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10l, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10w, listed inTable 1, or any combination thereof.

In some embodiments, the colon cancer is caused by a gastrointestinaldisorder, disease or condition. In one embodiment, the gastrointestinaldisorder, disease or condition may comprise colitis, Crohn's disease,irritable bowel syndrome, indeterminant colitis, infectious colitis,irritable bowel diseases, ulcerative colitis, ulcerative proctitis orothers as known to those skilled in the art.

In another embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofgastrointestinal disorder, disease or condition in a subject, comprisingadministering a compound of formula (I)-(XI), which in some embodimentsis a SERM, or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, ester, hydrate or any combination thereof,to the subject.

In some embodiments, treatment may comprise administration of otheragents, which treat colon cancer, such as, for example,azetidinone-based cholesterol absorption inhibitors, or others, as knownto those skilled in the art. In some embodiments, such treatment mayprecede, or follow that of the NRBAs of this invention, or be concurrenttherewith. In some embodiments, such methods may comprise administrationof a composition comprising the compound, or compounds, and optionallyother agents, which are useful in this context.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofhead and neck cancer in a subject, comprising administering a compoundof formula (I)-(XI), which in some embodiments is a SERM, or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, to the subject.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofliver cancer in a subject, comprising administering a compound offormula (I)-(XI), which in some embodiments is a SERM, or its prodrug,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,ester, hydrate or any combination thereof, to the subject.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofthyroid cancer in a subject, comprising administering a compound offormula (I)-(XI), which in some embodiments is a SERM, or its prodrug,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,ester, hydrate or any combination thereof, to the subject.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofkidney cancer in a subject, comprising administering a compound offormula (I)-(XI), which in some embodiments is a SERM, or its prodrug,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,ester, hydrate or any combination thereof, to the subject.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofpancreatic cancer in a subject, comprising administering a compound offormula (I)-(XI), which in some embodiments is a SERM, or its prodrug,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,ester, hydrate or any combination thereof, to the subject.

Melanomas are aggressive, frequently metastatic tumors derived fromeither melanocytes or melanocyte related nevus cells (“Cellular andMolecular Immunology” (1991) (eds) Abbas A. K., Lechtman, A. H., Pober,J. S.; W. B. Saunders Company, Philadelphia: pages 340-341). Melanomasmake up approximately three percent of all skin cancers and theworldwide increase in melanoma is unsurpassed by any other neoplasm withthe exception of lung cancer in women (“Cellular and MolecularImmunology” (1991) (eds) Abbas, A. K., Lechtiman, A. H., Pober, J. S.;W. B. Saunders Company Philadelphia pages: 340-342; Kirkwood andAgarwala (1993) Principles and Practice of Oncology 7:1-16). Even whenmelanoma is apparently localized to the skin, up to 30% of the patientswill develop systemic metastasis and the majority will die (Kirkwood andAgarwala (1993) Principles and Practice of Oncology 7:1-16). Classicmodalities of treating melanoma include surgery, radiation andchemotherapy. In the past decade immunotherapy and gene therapy haveemerged as new and promising methods for treating melanoma.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofmelanoma in a subject, comprising administering a compound of formula(I)-(XI), which in some embodiments is a SERM, or its prodrug, analog,isomer, metabolite, derivative, pharmaceutically acceptable salt,pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester,hydrate or any combination thereof, to the subject.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofskin disorder, disease or condition in a subject, comprisingadministering a compound of formula (I)-(XI), which in some embodimentsis a SERM, or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, ester, hydrate or any combination thereof,to the subject.

In one embodiment, skin disorder, disease or condition may comprise,dermatitis, melanoma, pruritis, psoriasis, skin atrophy.

In one embodiment, this invention provides methods of 1) improving thelipid profile of a subject; 2) reducing the circulating lipid levels ina subject; 3) increasing high density lipoprotein (HDL) cholesterollevels in a subject; 4) altering ratios of low density lipoprotein tohigh density lipoprotein levels in a subject; wherein said subject hasprostate cancer and is undergoing or has undergone ADT, wherein saidmethod comprises administering to said subject a compound of formula(I)-(XI) or its prodrug, ester, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof. Inanother embodiment, the method comprises administering a compositioncomprising the compound.

In another embodiment, the subject is undergoing or has undergone ADT.The terms “has undergone,” “undergoing”, and the like refer, in oneembodiment, to subjects that have recently (within the last 6 months) orare currently receiving any treatment or therapy known in the art thatreduces androgen levels in general or testosterone levels in particular.In another embodiment, the terms refer to a subject that received such atreatment or therapy more than 6 months previously. In one embodiment,the treatment or therapy is surgical. In another embodiment, thetreatment or therapy is medical. In another embodiment, the treatment ortherapy eliminates an androgen or a testosterone entirely, or belowdetectable levels. In another embodiment, the ADT is a side effect of atreatment or therapy not intended to reduce androgen or testosteronelevels. Each of these possibilities represents a separate embodiment ofthe present invention.

In another embodiment, ADT is used for treating prostate cancer, fordelaying the progression of prostate cancer, and for preventing and/ortreating the recurrence of prostate cancer, which comprise administeringLHRH analogs, reversible anti-androgens (such as bicalutamide orflutamide), anti-estrogens, anticancer drugs, 5-alpha reductaseinhibitors, aromatase inhibitors, progestins, selective androgenreceptor modulators (SARMS) or agents acting through other nuclearhormone receptors. In another embodiment, ADT is administered monthly,or every 3, 4, 6 or 12 months. In another embodiment, ADT isadministered every two weeks in the first month, then every four weeks.

In some embodiments, according to this aspect, such methods compriseadministering a compound of this invention to a subject that hasprostate cancer and is undergoing or has undergone ADT. In oneembodiment, the compound can be administered prior to the ADT. Inanother embodiment, the compound can be administered concurrent withADT. In another embodiment, the compound can be administered followingADT.

In some embodiments, the methods of this invention compriseadministering a compound of this invention in combination with the ADT,prior to the ADT or after the ADT as a preventive for all diseases inthis invention. In some embodiments, such compounds are SERMs. In oneembodiment the SERM is administered between 1-2 weeks before ADT. Inanother embodiment the SERM is administered between 2-4 weeks prior toADT. In another embodiment the SERM is administered between 1-2 monthsbefore ADT. In another embodiment the SERM is administered between 2-4months before ADT. In another embodiment the SERM is administeredbetween 4-6 months before ADT. In one embodiment the SERM isadministered between 1-2 weeks after ADT. In another embodiment the SERMis administered between 2-4 weeks after ADT. In another embodiment theSERM is administered between 1-2 months after ADT. In another embodimentthe SERM is administered between 2-4 months after ADT. In anotherembodiment the SERM is administered between 4-6 months after ADT.

In other embodiments, the present invention provides a method oftreating any disease, disorder, or symptom associated with ADT. In otherembodiments, the present invention provides a method of treating anydisease, disorder, or symptom associated with testosterone deprivation.Each disease, disorder, or symptom represents a separate embodiment ofthe present invention.

Papilloma viruses are non-enveloped DNA viruses that inducehyperproliferative lesions of the epithelia. The papilloma viruses arewidespread in nature and have been identified in higher vertebrates.Viruses have been characterized, amongst others, from humans, cattle,rabbits, horses, and dogs. Human papilloma viruses (HPV) have beenclassified into more than 80 types (Epidemiology and Biology of CervicalCancer. Seminars in Surgical Oncology 1999 16:203-211).

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset, reducing the recurrence of, or reducing the severity ofpapilloma in a subject, comprising administering a compound of formula(I)-(XI), which in some embodiments is a SERM, or its prodrug, analog,isomer, metabolite, derivative, pharmaceutically acceptable salt,pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester,hydrate or any combination thereof, to the subject.

Cross-talk has been shown to occur between endocrine-disruptingchemicals and cytokine signaling through estrogen receptors, suggestinga role for SERMs and/or other nuclear hormone binding agents in themodulation of the immune system and/or diseases thereof.

For example, tamoxifen, clomiphene and nafoxidine cause a decrease inviability of the estrogen receptor-negative T-lymphoblastic leukemiacell line CCRF/CEM, suggesting a role for antiestrogens in the clinicaltreatment of leukemia.

Leukemia is a malignant cancer of the bone marrow and blood andcomprises acute or chronic myelogenous, or acute or chronic lymphocytictype disease.

Standard treatment for leukemia usually involves chemotherapy and/orbone marrow transplantation and/or radiation therapy. Chemotherapyusually involves a combination of two or more anti-cancer drugs, withcommon combinations including cytarabine with either doxorubicin ordaunorubicin or mitoxantrone or thioguanine, mercaptopurine withmethotrexate, mitroxantrone with etoposide, asparaginase withvincristine, daunorubicin and prednisone, cyclophosphamide withvincristine, cytarabine and prednisone, cyclophosphamide withvincristine and prednisone, daunorubicin with cytarabine and thioguanineand daunorubicin with vincristine and prednisone.

In one embodiment, the invention provides a method of treating,preventing the recurrence, inhibiting, reducing the incidence of,delaying onset or reducing the severity of leukemia in a subject,comprising administering a compound of formula (I)-(XI) or its prodrug,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,ester, hydrate or any combination thereof, to the subject.

In some embodiments, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, or reducing pathogenesis of cancer. In another embodiment, thecancer comprises androgen AR dependent tumors (malignant or benign) suchas prostate cancer, breast cancer (male or female, operable orinoperable). In another embodiment the compounds adjunct to ADT fortreating prostate cancer; bladder cancers; brain cancers; bone tumors,colon cancer, endometrial cancer, liver cancer, lung cancer, lymphaticcancer, kidney cancer, osteosarcoma cancer, ovarian cancer, pancreascancer, penis cancer, skin cancer, thyroid cancer; and/orhormone-dependent cancers.

In some embodiments this invention provides a method of treating,suppressing, reducing the incidence or severity of, or prolongingremission of bladder cancer in a subject, the method comprisingadministering a NRBA or SERM of formula (I)-(XI) or its prodrug, analog,isomer, metabolite, derivative, pharmaceutically acceptable salt,pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester,hydrate or any combination thereof to the subject.

Existing therapies for bladder cancer may be combined with the therapiesprovided herein, including, cystectomy with or without administration ofmethotrexate, vinbiastine, doxorubicin, or cisplatin (M-VAC), or othersas known in the art.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for a) treating a bone related disorder; b) preventing a bonerelated disorder; c) suppressing a bone related disorder; d) inhibitinga bone related disorder; e) increasing a strength of a bone of asubject; f) increasing a bone mass in a subject; g) use forosteoclastogenesis inhibition.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for a) Accelerate bone repair; b) treating bone disorders; c)treating bone density loss; d) treating low bone mineral density (BMD);e) treating reduced bone mass; f) treating metabolic bone disease; g)promoting bone growth or regrowth; h) promoting bone restoration; i)promoting bone fracture repair; j) promoting bone remodeling; k)treating bone damage following reconstructive surgery including of theface, hip, or joints; l) enhancing of bone strength and function; m)increasing cortical bone mass; n) increasing trabecular connectivity.

In one embodiment, the invention provides a method of treating,preventing, reducing the severity of, delaying onset, reducing therecurrence of a bone-related disease or disorder in a subject,comprising administering a NRBA, which in some embodiments is a SERM, ofthis invention to the subject. In one embodiment, the subject isadministered a NRBA/SERM or composition comprising the same, wherein theNRBA/SERM is a of formula (I)-(XI) or its prodrug, ester, analog,isomer, metabolite, derivative, pharmaceutically acceptable salt,pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrateor any combination thereof. In some embodiments ER-β agonists are usefulin treating, preventing, reducing the severity of, delaying onset,reducing the recurrence of a bone-related disease or disorder in asubject. In another embodiment, ER-β agonist of this invention iscompound 3a, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3d, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3e, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3l,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3g, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 3j, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3i, listed inTable 1, or any combination thereof. In another embodiment, ER-β agonistof this invention is compound 4a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 4h, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 4u, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10o, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10f, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10l, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10w, listed inTable 1, or any combination thereof.

In one embodiment, the bone related disorder is a genetic disorder, orin another embodiment, is induced as a result of a treatment regimen fora given disease. For example, and in one embodiment, the compounds asherein described are useful in treating a bone-related disorder thatarises as a result of cancer metastasis to bone, or in anotherembodiment, as a result of androgen-deprivation therapy, for example,given in response to prostate carcinogenesis in the subject.

In one embodiment, the bone-related disorder is osteoporosis. In anotherembodiment, the bone-related disorder is osteopenia. In anotherembodiment, the bone-related disorder is increased bone resorption. Inanother embodiment, the bone-related disorder is bone fracture. Inanother embodiment, the bone-related disorder is bone frailty.

In another embodiment, the bone-related disorder is a loss of bonemineral density (BMD). In another embodiment, the bone-related disorderis any combination of osteoporosis, osteopenia, increased boneresorption, bone fracture, bone frailty and loss of BMD. Each disorderrepresents a separate embodiment of the present invention.

“Osteoporosis” refers, in one embodiment, to a thinning of the boneswith reduction in bone mass due to depletion of calcium and boneprotein. In another embodiment, osteoporosis is a systemic skeletaldisease, characterized by low bone mass and deterioration of bonetissue, with a consequent increase in bone fragility and susceptibilityto fracture. In osteoporotic patients, bone strength is abnormal, in oneembodiment, with a resulting increase in the risk of fracture. Inanother embodiment, osteoporosis depletes both the calcium and theprotein collagen normally found in the bone, in one embodiment,resulting in either abnormal bone quality or decreased bone density. Inanother embodiment, bones that are affected by osteoporosis can fracturewith only a minor fall or injury that normally would not cause a bonefracture. The fracture can be, in one embodiment, either in the form ofcracking (as in a hip fracture) or collapsing (as in a compressionfracture of the spine). The spine, hips, and wrists are common areas ofosteoporosis-induced bone fractures, although fractures can also occurin other skeletal areas. Unchecked osteoporosis can lead, in anotherembodiment, to changes in posture, physical abnormality, and decreasedmobility.

In one embodiment, the osteoporosis results from androgen deprivation.In another embodiment, the osteoporosis follows androgen deprivation. Inanother embodiment, the osteoporosis is primary osteoporosis. In anotherembodiment, the osteoporosis is secondary osteoporosis. In anotherembodiment, the osteoporosis is postmenopausal osteoporosis. In anotherembodiment, the osteoporosis is juvenile osteoporosis. In anotherembodiment, the osteoporosis is idiopathic osteoporosis. In anotherembodiment, the osteoporosis is senile osteoporosis.

In another embodiment, the primary osteoporosis is Type I primaryosteoporosis. In another embodiment, the primary osteoporosis is Type IIprimary osteoporosis. Each type of osteoporosis represents a separateembodiment of the present invention.

According to this aspect of the invention and in one embodiment, thebone-related disorder is treated with a compound as herein described, ora combination thereof. In another embodiment, other bone-stimulatingcompounds can be provided to the subject, prior to, concurrent with orfollowing administration of a compound or compounds as herein described.In one embodiment, such a bone stimulating compound may comprise naturalor synthetic materials.

In another embodiment, the invention provides, a method of reducing theincidence, inhibiting, suppressing, and treating osteoporosis, bonefractures and/or loss of bone mineral density (BMD) in a subject,comprising administering a NRBA/SERM of formula (I)-(XI), or itsprodrug, ester, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, hydrate or any combination thereof, or a composition comprisingthe same, thereby reducing the incidence, inhibiting, suppressing, andtreating osteoporosis, bone fractures and/or loss of bone mineraldensity (BMD) in the subject. In some embodiments ER-β agonists areuseful in reducing the incidence, inhibiting, suppressing, and treatingosteoporosis, bone fractures and/or loss of bone mineral density (BMD)in a subject In another embodiment, ER-β agonist of this invention iscompound 3a, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3d, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3e, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3l,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3g, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 3j, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3i, listed inTable 1, or any combination thereof. In another embodiment, ER-β agonistof this invention is compound 4a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 4h, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 4u, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10o, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10f, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 10w, listed in Table 1, orany combination thereof.

In one embodiment, the bone stimulating compound may comprise a bonemorphogenetic protein (BMP), a growth factor, such as epidermal growthfactor (EGF), a fibroblast growth factor (FGF), a transforming growthfactor (TGF, an insulin growth factor (IGF), a platelet-derived growthfactor (PDGF) hedgehog proteins such as sonic, indian and deserthedgehog, a hormone such as follicle stimulating hormone, parathyroidhormone, parathyroid hormone related peptide, activins, inhibins,follistatin, frizzled, frzb or frazzled proteins, BMP binding proteinssuch as chordin and fetuin, a cytokine such as IL-3, IL-7, GM-CSF, achemokine, such as eotaxin, a collagen, osteocalcin, osteonectin andothers, as will be appreciated by one skilled in the art.

In another embodiment, the compositions for use in treating a bonedisorder of this invention may comprise a compound or compounds asherein described, an additional bone stimulating compound, or compounds,and osteogenic cells. In one embodiment, an osteogenic cell may be astem cell or progenitor cell, which may be induced to differentiate intoan osteoblast. In another embodiment, the cell may be an osteoblast. Inanother embodiment, nucleic acids which encode bone-stimulatingcompounds may be administered to the subject, which is to be consideredas part of this invention.

In one embodiment, the methods of the present invention compriseadministering the compound for treating osteoporosis. In anotherembodiment, the methods of this invention comprise administering acompound in combination with SERMs for treating osteoporosis. In anotherembodiment, the SERMs are tamoxifene, 4-hydroxytamoxifene, idoxifene,toremifene, ospemifene, droloxifene, raloxifene, arzoxifene,bazedoxifene, PPT (1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole),DPN, lasofoxifene, pipendoxifene, EM-800, EM-652, nafoxidine,zindoxifene, tesmilifene, miproxifene phosphate, RU 58,688, EM 139, ICI164,384, ICI 182,780, clomiphene, MER-25, diethylstibestrol, coumestrol,genistein, GW5638, LY353581, zuclomiphene, enclomiphene, delmadinoneacetate, DPPE, (N,N-diethyl-2-{4-(phenylmethyl)-phenoxy}ethanamine),TSE-424, WAY-070, WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041,WAY-397, WAY-244, ERB-196, WAY-169122, MF-101, ERb-002, ERB-037,ERB-017, BE-1060, BE-380, BE-381, WAY-358, [18F]FEDNP, LSN-500307,AA-102, Ban zhi lian, CT-101, CT-102, or VG-101.

In another embodiment, the methods of the present invention compriseadministering the compounds of this invention, in combination withbisphosphonates such as alendronate, tiludroate, clodroniate,pamidronate, etidronate, alendronate, zolendronate, cimadronate,neridronate, minodronic acid, ibandronate, risedronate, orhomoresidronate for treating osteoporosis.

In another embodiment, the methods of the present invention compriseadministering the compound, in combination with Calcitonin such assalmon, Elcatonin, SUN-8577 or TJN-135 for treating osteoporosis.

In another embodiment, the methods of treating osteoporosis of thepresent invention comprise administering the compound of this invention,in combination with a) vitamin D or derivative such as ZK-156979; b)vitamin D receptor ligand and analogues such as calcitriol, topitriol,ZK-150123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299 orDP-035; c) estrogen, estrogen derivative, or conjugated estrogens; d)antiestrogen, progestins, or synthetic estrogen/progestins; e) RANKligand mAb such as denosumab formerly AMG162 (Amgen); f) ανβ3 Integrinreceptor antagonist; g) osteoclast vacuolar ATPase inhibitor; h)antagonist of VEGF binding to osteoclast receptors; i) calcium receptorantagonist; j) PTh (parathyroid hormone) and analogues, PTHrP analogues(parathyroid hormone-related peptide); k) Cathepsin K inhibitors(AAE581, etc.); l) strontium ranelate; m) tibolone; n) HCT-1026,PSK3471; o) gallium maltolate; p) nutropin AQ; q) prostaglandins (forosteo); r) p38 protein kinase inhibitor; s) bone morphogenetic protein;t) inhibitor of BMP antagonism; u) HMG-CoA reductase inhibitor; v)vitamin K or derivative; w) ipriflavone; x) fluoride salts; y) dietarycalcium supplement, and z) osteoprotegerin.

In one embodiment, the methods of this invention are useful in treatingdiseases or disorders caused by, or associated with a hormonal disorder,disruption or imbalance. In one embodiment, the hormonal disorder,disruption or imbalance comprises an excess of a hormone. In anotherembodiment, the hormonal disorder, disruption or imbalance comprises adeficiency of a hormone. In one embodiment, the hormone is a steroidhormone. In another embodiment, the hormone is an estrogen. In anotherembodiment, the hormone is an androgen. In another embodiment, thehormone is a glucocorticoid. In another embodiment, the hormone is acortico-steroid. In another embodiment, the hormone is LuteinizingHormone (LH). In another embodiment, the hormone is Follicle StimulatingHormone (FSH). In another embodiment, the hormone is any other hormoneknown in the art. In another embodiment, the hormonal disorder,disruption or imbalance is associated with menopause. In anotherembodiment, the hormonal disorder, disruption or imbalance is associatedwith andropause, andropausal vasomotor symptoms, andropausalgynecomastia, muscle strength and/or function, bone strength and/orfunction and anger. In another embodiment, hormone deficiency is aresult of specific manipulation, as a byproduct of treating a disease ordisorder in the subject. For example, the hormone deficiency may be aresult of androgen depletion in a subject, as a therapy for prostatecancer in the subject. Each possibility represents a separate embodimentof the present invention.

In another embodiment the invention is directed to treating sarcopeniaor cachexia, and associated conditions related thereto, for examplediseases or disorders of the bone.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for 1) treating a muscle wasting disorder; 2) preventing amuscle wasting disorder; 3) treating, preventing, suppressing,inhibiting or reducing muscle loss due to a muscle wasting disorder; 4)treating, preventing, inhibiting, reducing or suppressing muscle wastingdue to a muscle wasting disorder; and/or 5) treating, preventing,inhibiting, reducing or suppressing muscle protein catabolism due to amuscle wasting disorder; and/or treating, preventing, inhibiting,reducing or suppressing end stage renal disease; and/or 6) treating,preventing, inhibiting, reducing or suppressing fraility.

In another embodiment, the use of a compound for treating a subjecthaving a muscle wasting disorder, or any of the disorders describedherein, includes administering a pharmaceutical composition including acompound as herein described. In another embodiment, the administeringstep includes intravenously, intraarterially, or intramuscularlyinjecting to said subject said pharmaceutical composition in liquidform; subcutaneously implanting in said subject a pellet containing saidpharmaceutical composition; orally administering to said subject saidpharmaceutical composition in a liquid or solid form; or topicallyapplying to the skin surface of said subject said pharmaceuticalcomposition.

A muscle is a tissue of the body that primarily functions as a source ofpower. There are three types of muscles in the body: a) skeletalmuscle—the muscle responsible for moving extremities and external areasof the bodies; b) cardiac muscle—the heart muscle; and c) smoothmuscle—the muscle that is in the walls of arteries and bowel.

A wasting condition or disorder is defined herein as a condition ordisorder that is characterized, at least in part, by an abnormal,progressive loss of body, organ or tissue mass. A wasting condition canoccur as a result of a pathology such as, for example, cancer, or aninfection, or it can be due to a physiologic or metabolic state, such asdisuse deconditioning that can occur, for example, due to prolonged bedrest or when a limb is immobilized, such as in a cast. A wastingcondition can also be age associated. The loss of body mass that occursduring a wasting condition can be characterized by a loss of total bodyweight, or a loss of organ weight such as a loss of bone or muscle massdue to a decrease in tissue protein.

In one embodiment, “muscle wasting” or “muscular wasting”, used hereininterchangeably, refer to the progressive loss of muscle mass and/or tothe progressive weakening and degeneration of muscles, including theskeletal or voluntary muscles which control movement, cardiac muscleswhich control the heart, and smooth muscles. In one embodiment, themuscle wasting condition or disorder is a chronic muscle wastingcondition or disorder. “Chronic muscle wasting” is defined herein as thechronic (i.e. persisting over a long period of time) progressive loss ofmuscle mass and/or to the chronic progressive weakening and degenerationof muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by a muscle protein breakdown or degradation, by muscleprotein catabolism. Protein catabolism occurs because of an unusuallyhigh rate of protein degradation, an unusually low rate of proteinsynthesis, or a combination of both. Protein catabolism or depletion,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. The term “catabolism” has its commonly known meaning in theart, specifically an energy burning form of metabolism.

Muscle wasting can occur as a result of a pathology, disease, conditionor disorder. In one embodiment, the pathology, illness, disease orcondition is chronic. In another embodiment, the pathology, illness,disease or condition is genetic. In another embodiment, the pathology,illness, disease or condition is neurological. In another embodiment,the pathology, illness, disease or condition is infectious. As describedherein, the pathologies, diseases, conditions or disorders for which thecompounds and compositions of the present invention are administered arethose that directly or indirectly produce a wasting (i.e. loss) ofmuscle mass, that is a muscle wasting disorder.

In one embodiment, muscle wasting in a subject is a result of thesubject having a muscular dystrophie; muscle atrophy; X-linkedspinal-bulbar muscular atrophy (SBMA).

The muscular dystrophies are genetic diseases characterized byprogressive weakness and degeneration of the skeletal or voluntarymuscles that control movement. The muscles of the heart and some otherinvoluntary muscles are also affected in some forms of musculardystrophy. The major forms of muscular dystrophy (MD) are: duchennemuscular dystrophy, myotonic dystrophy, duchenne muscular dystrophy,becker muscular dystrophy, limb-girdle muscular dystrophy,facioscapulhumeral muscular dystrophy, congenital muscular dystrophy,oculopharyngeal muscular dystrophy, distal muscular dystrophy andemery-dreifuss muscular dystrophy.

Muscular dystrophy can affect people of all ages. Although some formsfirst become apparent in infancy or childhood, others may not appearuntil middle age or later. Duchenne MD is the most common form,typically affecting children. Myotonic dystrophy is the most common ofthese diseases in adults.

Muscle atrophy (MA) is characterized by wasting away or diminution ofmuscle and a decrease in muscle mass. For example, Post-Polio MA is amuscle wasting that occurs as part of the post-polio syndrome (PPS). Theatrophy includes weakness, muscle fatigue, and pain.

Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA—alsoknown as Kennedy's Disease). This disease arises from a defect in theandrogen receptor gene on the X chromosome, affects only males, and itsonset is in adulthood. Because the primary disease cause is an androgenreceptor mutation, androgen replacement is not a current therapeuticstrategy. There are some investigational studies where exogenoustestosterone propionate is being given to boost the levels of androgenwith hopes of overcoming androgen insensitivity and perhaps provide ananabolic effect. Still, use of supraphysiological levels of testosteronefor supplementation will have limitations and other potentially seriouscomplications.

Sarcopenia is a debilitating disease that afflicts the elderly andchronically ill patients and is characterized by loss of muscle mass andfunction. Further, increased lean body mass is associated with decreasedmorbidity and mortality for certain muscle-wasting disorders. Inaddition, other circumstances and conditions are linked to, and cancause muscle wasting disorders. For example, studies have shown that insevere cases of chronic lower back pain, there is paraspinal musclewasting.

Muscle wasting and other tissue wasting is also associated with advancedage. It is believed that general weakness in old age is due to musclewasting. As the body ages, an increasing proportion of skeletal muscleis replaced by fibrous tissue. The result is a significant reduction inmuscle power, performance and endurance.

Long term hospitalization due to illness or injury, or disusedeconditioning that occurs, for example, when a limb is immobilized, canalso lead to muscle wasting, or wasting of other tissue. Studies haveshown that in patients suffering injuries, chronic illnesses, burns,trauma or cancer, who are hospitalized for long periods of time, thereis a long-lasting unilateral muscle wasting, and a decrease in bodymass.

Injuries or damage to the central nervous system (CNS) are alsoassociated with muscle wasting and other wasting disorders. Injuries ordamage to the CNS can be, for example, caused by diseases, trauma orchemicals. Examples are central nerve injury or damage, peripheral nerveinjury or damage and spinal cord injury or damage. In one embodiment CNSdamage or injury comprise Alzheimer's diseases (AD); anger (mood);anorexia, anorexia nervosa, anorexia associated with aging and/orassertiveness (mood).

In another embodiment, muscle wasting or other tissue wasting may be aresult of alcoholism, and may be treated with the compounds andcompositions of the invention, representing embodiments thereof.

In one embodiment, the invention provides a use of a compound asdescribed herein or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof for thetreatment of a wasting disease, disorder or condition in a subject.

In one embodiment, the wasting disease, disorder or condition beingtreated is associated with chronic illness

This invention is directed to treating, in some embodiments, any wastingdisorder, which may be reflected in muscle wasting, weight loss,malnutrition, starvation, or any wasting or loss of functioning due to aloss of tissue mass.

In some embodiments, wasting diseases or disorders, such as cachexia;malnutrition, tuberculosis, leprosy, diabetes, renal disease, chronicobstructive pulmonary disease (COPD), cancer, end stage renal failure,sarcopenia, emphysema, osteomalacia, or cardiomyopathy, may be treatedby the methods of this invention, via the administration of a SARMcompound as herein described, compositions comprising the same, with orwithout additional drugs, compounds, or agents, which provide atherapeutic effect for the condition being treated.

In some embodiments, wasting is due to infection with enterovirus,Epstein-Ban virus, herpes zoster, HIV, trypanosomes, influenze,coxsackie, rickettsia, trichinella, schistosoma or mycobacteria, andthis invention, in some embodiments, provides methods of treatmentthereof.

Cachexia is weakness and a loss of weight caused by a disease or as aside effect of illness. Cardiac cachexia, i.e. a muscle protein wastingof both the cardiac and skeletal muscle, is a characteristic ofcongestive heart failure. Cancer cachexia is a syndrome that occurs inpatients with solid tumors and hematological malignancies and ismanifested by weight loss with massive depletion of both adipose tissueand lean muscle mass.

Cachexia is also seen in acquired immunodeficiency syndrome (AIDS),human immunodeficiency virus (HIV)-associated myopathy and/or muscleweakness/wasting is a relatively common clinical manifestation of AIDS.Individuals with HIV-associated myopathy or muscle weakness or wastingtypically experience significant weight loss, generalized or proximalmuscle weakness, tenderness, and muscle atrophy.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an infection ina subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound and an immunomodulatingagent, an anti-infective agent, a gene therapy agent, or a combinationthereof. In some embodiments, infections comprise actinomycosis,anaplasmosis, anthrax, aspergillosis, bacteremia, bacterial mycoses,bartonella infections, botulism, brucellosis, burkholderia infections,campylobacter infections, candidiasis, cat-scratch disease, chlamydiainfections, cholera, clostridium infections, coccidioidomycosis, crossinfection, cryptococcosis, dermatomycoses, diphtheria, ehrlichiosis,Escherichia coli infections, fasciitis, necrotizing, Fusobacteriuminfections, gas gangrene, gram-negative bacterial infections,gram-positive bacterial infections, histoplasmosis, impetigo, Klebsiellainfections, legionellosis, leprosy, leptospirosis, Listeria infections,lyme disease, maduromycosis, melioidosis, mycobacterium infections,mycoplasma infections, mycoses, nocardia infections, onychomycosis,plague, pneumococcal infections, pseudomonas infections, psittacosis, qfever, rat-bite fever, relapsing fever, rheumatic fever, Rickettsiainfections, rocky mountain spotted fever, salmonella infections, scarletfever, scrub typhus, sepsis, sexually transmitted diseases,Staphylococcal infections, Streptococcal infections, tetanus, tick-bornediseases, tuberculosis, tularemia, typhoid fever, typhus, louse-borne,vibrio infections, yaws, yersinia infections, zoonoses, zygomycosis,acquired immunodeficiency syndrome, adenoviridae infections, alphavirusinfections, arbovirus infections, borna disease, bunyaviridaeinfections, caliciviridae infections, chickenpox, coronaviridaeinfections, coxsackievirus infections, cytomegalovirus infections,dengue, DNA virus infections, ecthyma, contagious, encephalitis,arbovirus, Epstein-ban virus infections, erythema infectiosum,hantavirus infections, hemorrhagic fevers, viral hepatitis, viral humanherpes simplex, herpes zoster, herpes zoster oticus, herpesviridaeinfections, infectious mononucleosis, human-lassa fever, measles,molluscum, contagiosum, mumps, paramyxoviridae infections, phlebotomusfever, polyomavirus infections, rabies, respiratory syncytial virusinfections, rift valley fever, RNA virus infections, rubella, slow virusdiseases, smallpox, subacute sclerosing panencephalitis, tumor virusinfections, warts, west nile fever, virus diseases, yellow fever,amebiasis, anisakiasis, ascariasis, babesiosis, blastocystis hominisinfections, bug bite, cestode infections, chagas disease,cryptosporidiosis, cyclosporiasis, cysticercosis, dientamoebiasis,diphyllobothriasis, dracunculiasis, echinococcosis, ectoparasiticinfestations, filariasis, giardiasis, helminthiasis, hookworminfections, larva migrans, leishmaniasis, lice infestations, loiasis,malaria, mite infestations, myiasis, onchocerciasis, protozoaninfections, scabies, schistosomiasis, skin diseases, parasitic,strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis,trichomonas infections, trypanosomiasis, trypanosomiasis, african, orwhipworm infections.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with amusculoskeletal disease in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundand an anti-cancer agent, an immunomodulating agent, an antidiabeticagent, an agent treating the central nervous system, an agent treating ametabolic disease, an agent treating a wasting disease, a gene therapyagent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, musculoskeletal diseasescomprise achondroplasia, acquired hyperostosis syndrome,acrocephalosyndactylia, arthritis, arthrogryposis, arthropathy,neurogenic bursitis, cartilage diseases, cleidocranial dysplasia,clubfoot, compartment syndromes, craniofacial dysostosis,craniosynostoses, dermatomyositis, Dupuytren's contracture, dwarfism,Ellis Van Creveld syndrome, enchondromatosis, eosinophilia-myalgiasyndrome, exostoses, fasciitis, fatigue syndrome, fibromyalgia, fibrousdysplasia of bone, fibrous dysplasia, polyostotic, flatfoot, footdeformities, Freiberg's disease, funnel chest, Goldenhar syndrome, gout,hallux valgus, hip dislocation, hyperostosis, intervertebral diskdisplacement, kabuki make-up syndrome, Klippel-Feil syndrome,Langer-Giedion syndrome, Legg-Perthes disease, lordosis, mandibulofacialdysostosis, melorheostosis, mitochondrial myopathies, muscle cramp,muscle spasticity, muscular dystrophies, musculoskeletal abnormalities,musculoskeletal diseases, myositis, myositis ossificans, myotubularmyopathy, osteitis deformans, osteoarthritis, osteochondritis,osteogenesis imperfecta, osteomyelitis, osteonecrosis, osteopetrosis,osteoporosis, poland syndrome, polychondritis, relapsing, polymyalgiarheumatica, polymyositis, rhabdomyolysis, rheumatic diseases, Russellsilver syndrome, Scheuermann's disease, scoliosis, Sever'sdisease/calceneal apophysitis, spinal diseases, spinal osteophytosis,spinal stenosis, spondylitis, ankylosing, spondylolisthesis, sprengel'sdeformity, synovitis, tendinopathy, tennis elbow, tenosynovitis,thanatophoric dysplasia, or Tietze's syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a digestivesystem disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the central nervous system, an agent treating thegastrointestinal system, an anti-infective agent, an agent treating ametabolic disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,gastrointestinal diseases comprise adenomatous polyposis coli, Alagillesyndrome, anus diseases, appendicitis, barrett esophagus, biliaryatresia, biliary tract diseases, Caroli disease, celiac disease,cholangitis, cholecystitis, cholelithiasis, colitis, ulcerative, Crohn'sdisease, deglutition disorders, duodenal ulcer, dysentery,enterocolitis, pseudomembranous, esophageal achalasia, esophagealatresia, esophagitis, exocrine pancreatic insufficiency, fatty liver,fecal incontinence, gastritis, gastritis, hypertrophic, gastroenteritis,gastroesophageal reflux, gastroparesis, hemorrhoids, hepatic veinthrombosis, hepatitis, hepatitis, chronic, hernia, diaphragmatic,hernia, hiatal, Hirschsprung disease, hypertension (HTN), portal,inflammatory bowel diseases, intestinal diseases, intestinal neoplasms,intestinal neuronal dysplasia, intestinal obstruction, irritable bowelsyndrome, lactose intolerance, liver cirrhosis, liver diseases, meckeldiverticulum, pancreatic diseases, pancreatic neoplasms, pancreatitis,peptic ulcer, Peutz-Jeghers syndrome, proctitis, rectal diseases, rectalprolapse, short bowel syndrome, tracheoesophageal fistula, whippledisease, or Zollinger-Ellison syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a stomatognathicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an anti-infective agent,an agent treating a wasting disease, a gene therapy agent, an agenttreating the endocrine system, vitamins, or a combination thereof. Insome embodiments, stomatognathic diseases comprise ankyloglossia,bruxism, burning mouth syndrome, cheilitis, cherubism, cleft lip,dentigerous cyst, gingivitis, glossitis, benign migratory, herpeslabialis, Ludwig's angina, macroglossia, Melkersson-Rosenthal syndrome,periodontal diseases, Pierre Robin syndrome, prognathism, salivary glanddiseases, sialorrhea, stomatitis, aphthous, temporomandibular jointdisorders, temporomandibular joint dysfunction syndrome, or xerostomia.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a respiratorytract disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an agent treating thecentral nervous system, an agent treating the cardiovascular system, ananti-infective agent, an agent treating a wasting disease, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, respiratory tract diseasescomprise airway obstruction, apnea, asbestosis, asthma, asthma-inducedmuscle weakness or bone weakness, atelectasis, berylliosis, bronchialdiseases, bronchiectasis, bronchiolitis, bronchiolitis obliteransorganizing pneumonia, bronchitis, bronchopulmonary dysplasia, chronicobstructive pulmonary disease (COPD), common cold, cough, empyema,pleural, epiglottitis, glucocorticoid (GC)-induced myopathy orosteopenia hemoptysis, hypertension, pulmonary, hyperventilation,kartagener syndrome, lung abscess, lung diseases, meconium aspirationsyndrome, pleural effusion, pleurisy, pneumonia, pneumothorax, pulmonaryalveolar proteinosis, pulmonary disease, chronic obstructive, pulmonaryedema, pulmonary embolism, pulmonary emphysema, pulmonary fibrosis,respiratory distress syndrome, newborn-respiratory hypersensitivity,respiratory tract infections, rhinoscleroma, scimitar syndrome, severeacute respiratory syndrome, silicosis, sleep apnea, central stridor,tracheal stenosis, decreased muscle mass or bone mass due to asthma,wasting in chronic obstructive pulmonary disease (COPD), Wegener'sgranulomatosis, or whooping cough.

Lung diseases include diseases such as chronic obstructive pulmonarydisease (COPD), cystic fibrosis and interstitial lung disease. A commoncharacteristic of these diseases is the decreased capacity of lungs toexchange oxygen and carbon dioxide. This causes the patient to breathefaster which increases the energy the patient must expend in order toobtain enough oxygen. Various respiratory syndromes interfere with theability of the lungs to adequately exchange gas with the atmosphere.These respiratory problems are a major cause of mortality and morbidity.

In another embodiment, the invention provides a method of treating,preventing, inhibiting reducing the incidence of lung diseases,disorders or conditions in a subject, comprising administering apharmaceutical composition comprising a SERM of formula (I)-(XI) or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, thereby treating,preventing, inhibiting reducing the incidence of inflammatory conditionsin a subject.

In some embodiments, the lung diseases, disorders or conditions maycomprise asthma, chronic obstructive pulmonary disease (COPD), cysticfibrosis, hemorrhagic shock, lung cancer or pleurisy.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with anotorhinolaryngologic disease in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundand an anti-cancer agent, an immunomodulating agent, an anti-infectiveagent, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, otorhinolaryngologic diseases comprisecholesteatoma, middle ear, croup, deafness, epistaxis, hearing loss,hyperacusis, labyrinthitis, laryngitis, laryngomalacia, laryngostenosis,mastoiditis, Meniere's disease, nasal obstruction, nasal polyps, otitis,otorhinolaryngologic diseases, otosclerosis, pharyngitis, presbycusis,retropharyngeal abscess, rhinitis, sinusitis, tinnitus, tonsillitis,tympanic membrane perforation, vestibular neuronitis, vocal cordparalysis, or voice disorders.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a nervous systemdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an agent treating thecentral nervous system, an anti-infective agent, an agent treating ametabolic disease, an agent treating a wasting disease, a gene therapyagent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, nervous system diseasescomprise autonomic nervous system diseases, central nervous systemdiseases, cranial nerve diseases, demyelinating diseases, nervous systemmalformations, neurologic manifestations, or neuromuscular diseases.

In some embodiments, autonomic nervous system diseases comprisecausalgia, or reflex sympathetic dystrophy.

In some embodiments, central nervous system diseases compriseAlzheimer's disease, arachnoiditis, brain abscess, brain ischemia,central nervous system infections, cerebral palsy, cerebrovasculardisorders, corticobasal ganglionic degeneration (CBGD),Creutzfeldt-Jakob syndrome, Dandy-Walker syndrome, dementia,encephalitis, encephalomyelitis, epilepsy, epilepsy induced hypogonadaland/or hypermetabolic state, essential tremor, Friedreich ataxia,Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz syndrome,Huntington disease, hydrocephalus, hypoxia, insomnia, ischemic attack,kuru, Landau-Kleffner syndrome, Lewy Body disease, Machado-Josephdisease, meige syndrome, meningitis, bacterial meningitis, viral,migraine disorders, movement disorders, multiple system atrophy,myelitis, olivopontocerebellar atrophies, Parkinson's disease,parkinsonian disorders, poliomyelitis, postpoliomyelitis syndrome, priondiseases, pseudotumor cerebri, Shy-Drager syndrome, spasms, infantile,spinal cord diseases, supranuclear palsy, syringomyelia, thalamicdiseases, tic disorders, tourette syndrome, or uveomeningoencephaliticsyndrome. In some embodiments, the central nervous system disease iscystic fibrosis induced hypogonadal state.

In some embodiments, cranial nerve diseases comprise bell palsy, cranialnerve diseases, facial hemiatrophy, facial neuralgia, glossopharyngealnerve diseases, Moebius syndrome, or trigeminal neuralgia.

In some embodiments, central nervous system diseases comprise injuriesor damage to the central nervous system (CNS). In some embodiments,injuries or damage to the CNS may be associated with muscle wastingdisorders. Injuries or damage to the CNS can be, for example, caused bydiseases, trauma or chemicals. Examples are central nerve injury ordamage, peripheral nerve injury or damage and spinal cord injury ordamage.

Studies involving patients with spinal cord injuries (SCI) have shownthat central neurotransmitters may be altered after SCI causinghypothalamus-pituitary-adrenal axis dysfunction, whose disruption led toa significant decrease in testosterone and other hormone levels. SCI orother acute illness or trauma characteristically includes heightenedcatabolism in conjunction with the lowered anabolic activity resultingin a condition that is prone to loss of lean body tissue, which is oftenaccompanied by disturbed nutrient utilization. The effects of the lossof lean body mass include the development of wounds and impaired healingmechanisms, further compounding the problem. Because of poor nutritionand protein combined with immobilization, patients with spinal cordinjury are at high risk for bed sores.

In one embodiment, a wide variety of injuries of the CNS may be treatedby the methods of the present invention. CNS injury may refer, in oneembodiment, to a breakdown of the membrane of a nerve cell, or, inanother embodiment, to the inability of the nerve to produce andpropagate nerve impulses, or in another embodiment, to the death of thecell. An injury includes damage that directly or indirectly affects thenormal functioning of the CNS. The injury may be a structural, physical,or mechanical impairment and may be caused by physical impact, as in thecase of a crushing, compression, or stretching of nerve fibers.Alternatively, the cell membrane may be destroyed by or degraded by anillness, a chemical imbalance, or a physiological malfunction such asanoxia (e.g., stroke), aneurysm, or reperfusion. A CNS injury includes,for example and without limitation, damage to retinal ganglion cells, atraumatic brain injury, a stroke-related injury, a cerebralaneurism-related injury, a spinal cord injury, including monoplegia,diplegia, paraplegia, hemiplegia and quadriplegia, a neuroproliferativedisorder, or neuropathic pain syndrome.

In another embodiment, the invention provides a method of treating,preventing, suppressing, inhibiting, or reducing the incidence ofcentral nervous system (CNS) disorder, disease or condition in amammalian subject comprising administering a compound of formula(I)-(XI) or its prodrug, ester, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof to thesubject.

With injury to the spinal cord of a mammal, connections between nervesin the spinal cord are broken. Such injuries block the flow of nerveimpulses for the nerve tracts affected by the injury, with a resultingimpairment to both sensory and motor function. Injuries to the spinalcord may arise from compression or other contusion of the spinal cord,or a crushing or severing of the spinal cord. A severing of the spinalcord, also referred to herein as a “transection,” may be a completesevering or, may be an incomplete severing of the spinal cord.

In some embodiments, the methods of treating a subject suffering form aCNS injury or, in other embodiments, spinal cord injury, may beaccompanied by treatment of the subject with electrical stimulation ofthe injured site and the administration of a purine nucleoside, oranalog thereof, for example as described in United States PatentApplication Publication Number 20040214790A1.

In some embodiments, demyelinating diseases compriseadrenoleukodystrophy, alexander disease, canavan disease, demyelinatingdisease, diffuse cerebral sclerosis of schilder, leukodystrophy-globoidcell, leukodystrophy-metachromatic, multiple sclerosis, or neuromyelitisoptica.

In some embodiments, nervous system malformations comprise Arnold-Chiarimalformation, Charcot-Marie-Tooth disease, encephalocele, hereditarymotor and sensory neuropathies, septo-optic dysplasia, spina bifidaocculta, or spinal dysraphism.

In some embodiments, neurologic manifestations comprise agnosia,amnesia, anomia, aphasia, apraxias, back pain, Brown-Sequard syndrome,cerebellar ataxia, chorea, communication disorders, confusion,dizziness, dyslexia, dystonia, facial paralysis, fasciculation, gaitdisorders, neurologic-headache, hemiplegia, memory disorders, mentalretardation, mutism, myoclonus, neck pain, nonverbal learning disorder,olfaction disorders, pain, paralysis, phantom limb, prosopagnosia,quadriplegia, seizures, spasm, speech disorders, synesthesia tardivedyskinesia, taste disorders, torticollis, tremor, trismus,unconsciousness, or vertigo.

In some embodiments, neuromuscular diseases comprise. amyotrophiclateral sclerosis, brachial plexus neuritis, brachial plexusneuropathies, bulbar palsy, carpal tunnel syndrome, cubital tunnelsyndrome, diabetic neuropathies, dysautonomia, guillain, barre syndrome,hereditary sensory and autonomic neuropathies, miller fisher syndrome,motor neuron disease, muscular atrophy, spinal, myasthenia gravis,myopathies, structural, congenital, nerve compression syndromes,neuralgia, neuromuscular diseases, paralyses, familial periodic,peripheral nervous system diseases, poems syndrome, polyneuropathies,polyradiculopathy, refsum disease, sciatica, spinal muscular atrophiesof childhood, stiff-person syndrome, thoracic outlet syndrome, or ulnarnerve compression syndromes.

In one embodiment, methods of treating a subject with a nervous systemdisease encompass treating any secondary conditions in the subject,which arise due to the subject having a nervous system disease, some ofwhich are described herein.

The compounds of this invention may be useful for the treatment oramelioration of conditions affecting the neural retina. Estrogen mayhave neuroprotective effects in the retina (see for example InvestOphthal Vis Sci 38:1193-1202 (1997) and Invest Ophthal Vis Sci44(7):3155-3162 (2003)), and estrogen receptors are found in the innerretina as well as the choroid (Br J Ophthalmol 85:877-882 (2001). TheNRBAs of the present invention may be useful in treating the eye for, orprotecting against local ischemia or degenerative events that include,but are not limited to, macular degeneration, glaucoma, diabeticretinopathy, retinitis pigmentosa and other retinal degenerationresulting from genetic defects, trauma or environmental exposure.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an ophthalmicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a NRBA/SERM compoundand an anti-cancer agent, an immunomodulating agent, an agent treatingthe cardiovascular system, an anti-infective agent, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodimentsophthalmic disease comprise acute zonal occult outer retinopathy,abnormal color vision, Adie syndrome, albinism, ocular-amaurosis, fugax,amblyopia, aniridia, anisocoria, anterior ischemic optic neuropathy,anophthalmos, aphakia, asthenopia astigmatism, autoimmune diseaseblepharitis, blepharoptosis, blepharospasm, blindness, cataract, senilecataract central chorioretinopathy chalazion, chorioretinitis,chorioretinal hemorrhage, choroideremia, coloboma, color vision defects,conjunctivitis, corneal diseases, corneal dystrophies, corneal edema,corneal ulcer, corneal opacity, corneal erosion, corneal endothelialcell degeneration and dystrophy or loss of endothelial cell, cornealdystrophy or degeneration, detachment of corneal epithelium, epidemickeratoconjunctivitis, chalazion, central nerve diseases, central retinalartery or vein occlusion, arteriosclerosis of retinal artery, photopsia,diabetic retinopathy, chorioretinal atrophy, diabetic retinopathy,diplopia, distichiasis, dry eye syndromes, Duane retraction syndrome,ectropion, entropion, esotropia, exfoliation syndrome, exotropia, eyehemorrhage, eye neoplasms, eyelid diseases, floaters, general fibrosissyndrome, glaucoma, high tension glaucoma, normal tension glaucoma,gyrate atrophy, hemianopsia, Hermanski-Pudlak syndrome, hordeolum,Horner syndrome, hysteria hyperopia, hyphema, iridocyclitis iritis,Kearns-Sayer syndrome, keratitis, keratoconus, lacrimal apparatusdiseases, lacrimal duct obstruction, lens diseases, lowering in dynamicvisual activity, macular degeneration, macular hole microphthalmos,myopia, nystagmus, narrowing of visual field due to various kinds ofdiseases pathologic, ocular motility disorders, oculomotor nervediseases, ophthalmoplegia, optic atrophies, optic nerve diseases, opticneuritis, optic neuropathy, optic nerve atrophy orbital cellulitis,papilledema, peters anomaly, presbyopia, psychosis pterygium, pupildisorders, refractive errors, retinal detachment, retinal diseases,retinal vein occlusion, retinal and choroidal neovascular diseases,cataract due to removal of ovary, cataract due to TGFβ, macularfibrosis, macular epiretinal membrane, refractive error retinal tear,retinitis proliferans, pigmentary retinal degeneration retinitispigmentosa, retinopathy of prematurity, retinoschisis, scleritis, senilemacular degeneration scotoma, strabismus, Thygeson's superficialpunctate keratitis, trachoma, uveitis, white dot syndrome, visiondisorders, or vitreous disorders, diseases due to cerebral pituitarygland disorder and imbalance of hormones, diseases due to gene disorderand diseases due to immune disorder, the method comprising administeringa NRBA or SERM of formula (I)-(XI) or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof to the subject.

In some embodiments ER-β agonists are useful in treating, reducing theincidence, delaying the onset or progression, or reducing and/orabrogating the symptoms associated with an ophthalmic disease in asubject. In another embodiment, ER-β agonist of this invention iscompound 3a, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3d, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3e, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3l,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3g, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 3j, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3i, listed inTable 1, or any combination thereof. In another embodiment, ER-β agonistof this invention is compound 4a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 4h, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 4u, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10o, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10f, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10l, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10w, listed inTable 1, or any combination thereof.

In another embodiment, the methods of treating eye diseases compriseadministering a composition comprising the compounds of this inventionto the subject, wherein the composition is in the form of eye drops, eyewash, ointments, conjunctival injections, or contact lens adsorbents. Inanother embodiment, the methods of treating eye diseases comprisesadministering a composition comprising the compounds of this inventionin the form of a tablet, capsule, liquid, syrup, injection, hap,ointment, eye drops, suppository, and the like, and administered orally,or non-orally such as injection, locally such as dropping to eye, etc.The effective ingredient may be vaporized and inhaled, for examplethrough the nose, mouth or trachea.

In some embodiment, the methods of treating eye diseases compriseadministering a composition comprising the compounds of this inventionand any other compound, which is useful in treating the indicatedconditions, as known in the art.

In some embodiment, eye drops and eye wash comprise water-solubilizedcompounds (I)-(XI) of this invention, which are, in one embodiment,dissolved in sterilized distilled water, BSS Plus, and/or physiologicalsaline. In another embodiment, additives are added comprisingexcipients, carriers, pH controllers, isotonic agents, preservatives,glutathione, glucose, various kind of salt(s), stabilizers,refrigerants, antioxidants, antiseptic agents, or any combinationthereof. In another embodiment, the eye drops and eye wash comprisehydroxypropylmethyl cellulose, carboxymethyl cellulose or its sodiumsalt, polypyrrolidone, polyvinylpyrrolidone (this is added and heated),or any combination thereof.

In some embodiments, the compounds of this invention have low solubilityin water. In one embodiment, the compounds may be water solubilized byusing cyclodextrin. In another embodiment α-cyclodextrin is used. Inanother embodiment β cyclodextrin is used. In another embodiment, δcyclodextrin is used. In another embodiment, hydroxyalkylated βcyclodextrin is used.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a dermatologicaldisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound andanti-cancer agent, an immunomodulating agent, an agent treating adermatological disorder, an anti-infective agent, a gene therapy agent,an agent treating the endocrine system, vitamins, or a combinationthereof. In some embodiments, dermatological disorders comprise acne,actinic keratosis, alopecia, androgenic alopecia, alopecia areata,alopecia secondary to chemotherapy, alopecia secondary to radiationtherapy, alopecia induced by scarring, alopecia induced by stress,angioma, athlete's foot, aquagenic pruritus, atopic dermatitis,baldness, premature baldness, male pattern baldness, androgenicbaldness, basal cell carcinoma, burns, bed sore, Behcet's disease,blepharitis, boil, Bowen's disease, bullous pemphigoid, canker sore,carbuncles, cellulitis, chloracne, chronic dermatitis of the hands andfeet, dyshidrosis, cold sores, contact dermatitis, creeping eruption,dandruff, dermatitis, dermatitis herpetiformis, dermatofibroma, diaperrash, eczema, epidermolysis bullosa, erysipelas, erythroderma, frictionblister, genital wart, hidradenitis, suppurativa, hives, hyperhidrosis,ichthyosis, impetigo, jock itch, Kaposi's sarcoma, keloid,keratoacanthoma, keratosis pilaris, lice infection, lichen planus,lichen simplex chronicus, lipoma, lymphadenitis, malignant melanoma,melasma, miliaria, molluscum contagiosum, nummular dermatitis, paget'sdisease of the nipple, pediculosis, pemphigus, perioral dermatitis,photoallergy, photosensitivity, pityriasis rosea, pityriasis rubrapilaris, psoriasis, raynaud's disease, ring worm, rosacea, scabies,scleroderma, sebaceous cyst, seborrheic keratosis, seborrhoeicdermatitis, shingles, skin cancer, skin tags, spider veins, squamouscell carcinoma, stasis dermatitis, tick bite, tinea barbae, tineacapitis, tinea corporis, tinea cruris, tinea pedis, tinea unguium, tineaversicolor, tinea, tungiasis, vitiligo, or warts.

In one embodiment, the dermatological disorder is a wound or a burn. Insome embodiments, wounds and/or ulcers are found protruding from theskin or on a mucosal surface or as a result of an infarction in anorgan. A wound may be a result of a soft tissue defect or a lesion or ofan underlying condition. In one embodiment, the term “wound” denotes abodily injury with disruption of the normal integrity of tissuestructures. The term is also intended to encompass the terms “sore”,“lesion”, “necrosis” and “ulcer”. In one embodiment, the term “sore”refers to any lesion of the skin or mucous membranes and the term“ulcer” refers to a local defect, or excavation, of the surface of anorgan or tissue, which is produced by the sloughing of necrotic tissue.Lesion generally relates to any tissue defect. Necrosis is related todead tissue resulting from infection, injury, inflammation orinfarctions. All of these are encompassed by the term “wound”, whichdenotes any wound at any particular stage in the healing processincluding the stage before any healing has initiated or even before aspecific wound like a surgical incision is made (prophylactictreatment).

Examples of wounds which can be prevented and/or treated in accordancewith the present invention are, e.g., aseptic wounds, contused wounds,incised wounds, lacerated wounds, non-penetrating wounds (i.e. wounds inwhich there is no disruption of the skin but there is injury tounderlying structures), open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds, subcutaneous wounds, etc.Examples of sores are bed sores, canker sores, chrome sores, cold sores,pressure sores etc. Examples of ulcers are, e.g., peptic ulcer, duodenalulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemiculcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer,submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer,veneral ulcer, e.g. caused by gonorrhoea (including urethritis,endocervicitis and proctitis). Conditions related to wounds or soreswhich may be successfully treated according to the invention are burns,anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae,folliculitis, impetigo contagiosa, or impetigo bullosa, etc. There isoften a certain overlap between the use of the terms “wound” and “ulcer”and “wound” and “sore” and, furthermore, the terms are often used atrandom. Therefore as mentioned above, in the present context the term“wounds” encompasses the term “ulcer”, “lesion”, “sore” and“infarction”, and the terms are indiscriminately used unless otherwiseindicated.

The kinds of wounds to be treated according to the invention includealso i) general wounds such as, e.g., surgical, traumatic, infectious,ischemic, thermal, chemical and bullous wounds; ii) wounds specific forthe oral cavity such as, e.g., post-extraction wounds, endodontic woundsespecially in connection with treatment of cysts and abscesses, ulcersand lesions of bacterial, viral or autoimmunological origin, mechanical,chemical, thermal, infectious and lichenoid wounds; herpes ulcers,stomatitis aphthosa, acute necrotising ulcerative gingivitis and burningmouth syndrome are specific examples; and iii) wounds on the skin suchas, e.g., neoplasm, burns (e.g. chemical, thermal), lesions (bacterial,viral, autoimmunological), bites and surgical incisions. Another way ofclassifying wounds is as i) small tissue loss due to surgical incisions,minor abrasions and minor bites, or as ii) significant tissue loss. Thelatter group includes ischemic ulcers, pressure sores, fistulae,lacerations, severe bites, thermal burns and donor site wounds (in softand hard tissues) and infarctions.

In other aspects of the invention, the wound to be prevented and/ortreated is selected from the group consisting of aseptic wounds,infarctions, contused wounds, incised wounds, lacerated wounds,non-penetrating wounds, open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds and subcutaneous wounds.

Other wounds which are of importance in connection with the presentinvention are wounds like ischemic ulcers, pressure sores, fistulae,severe bites, thermal burns and donor site wounds.

In one embodiment, the compound as described herein is useful in woundhealing as an adjunct to physical therapy/rehabilitation, as an anabolicagent. In another embodiment, the compound as described herein is usefulin promoting healing of anterior

cruciate ligament (ACL) or medial cruciate ligament (MCL) injuries, oraccelerating recovery after ACL or MCL surgery. In another embodiment,the compound as described herein is useful in enhancing athleticperformance. In another embodiment, the compound as described herein isuseful in treating burns. In another embodiment, the compound asdescribed herein is useful in stimulating cartilage regrowth. In anotherembodiment, the compound as described herein is useful in preventing,treating, or reversing of catabolism associated with prolonged criticalillness, pulmonary dysfunction, ventilator dependency, aging, AIDS,trauma, surgery, congestive heart failure, cardiac myopathy, burns,cancer, COPD. In another embodiment, the compound as described herein isuseful in preventing or reversing protein catabolism due to trauma. Inanother embodiment, the compound as described herein is useful as a)adjunct to cauterization therapy (laser or radio) as is used in surgeryto promote wound healing, b) adjunct to cryotherapy to promote woundhealing, c) adjunct to chemotherapy to prevent side effects such asalopecia, hypogonadism, muscle wasting, osteopenia, osteoporosis,sarcopenia, increased LDL, TG or total cholesterol, decreased HDL. Inanother embodiment, the compound as described herein is useful inchronic catabolic state (coma, wasting conditions, starvation, eatingdisorders); concomitant bone fracture and muscle damage;

critical illness in which muscle or bone wasting are apparent; and/orconnective tissue diseases and disorders.

Ischemic ulcers and pressure sores are wounds, which normally only healvery slowly and especially in such cases an improved and more rapidhealing is of course of great importance for the patient. Furthermore,the costs involved in the treatment of patients suffering from suchwounds are markedly reduced when the healing is improved and takes placemore rapidly.

Donor site wounds are wounds which e.g. occur in connection with removalof hard tissue from one part of the body to another part of the bodye.g. in connection with transplantation. The wounds resulting from suchoperations are very painful and an improved healing is therefore mostvaluable.

The term “skin” is used in a very broad sense embracing the epidermallayer of the skin and in those cases where the skin surface is more orless injured also the dermal layer of the skin. Apart from the stratumcorneum, the epidermal layer of the skin is the outer (epithelial) layerand the deeper connective tissue layer of the skin is called the dermis.

In some embodiments, burns are associated with reduced testosteronelevels, and hypgonadism is associated with delayed wound healing. In oneembodiment, the methods of this invention, provide for treating asubject suffering from a wound or a burn.

In some embodiments, the present invention provides a method forpromoting healing of anterior cruciate ligament (ACL) or medial cruciateligament (MCL) injuries, or accelerating recovery after ACL or MCLsurgery.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an endocrinedisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound andanti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating a dermatological disorder, anagent treating the central nervous system, an anti-infective agent, anagent treating the liver, an agent treating the kidney, an agenttreating a metabolic disease, an agent treating a wasting disease, agene therapy agent, an agent treating the endocrine system, vitamins, ora combination thereof. In some embodiments, endocrine disorders compriseacromegaly, Addison disease, adrenal gland diseases, adrenalhyperplasia, congenital, androgen-insensitivity syndrome, congenitalhypothyroidism, Cushing syndrome, diabetes insipidus, diabetes mellitus,diabetes mellitus-type 1, diabetes mellitus-type 2, diabetic,ketoacidosis, empty Sella syndrome, endocrine gland neoplasms, endocrinesystem diseases, gigantism, gonadal disorders, graves disease,hermaphroditism, hyperaldosteronism, hyperglycemic hyperosmolarnonketotic coma, hyperpituitarism, hyperprolactinemia, hyperthyroidism,hypogonadism, hypopituitarism, hypothyroidism, Kallmann syndrome, Nelsonsyndrome, parathyroid diseases, pituitary diseases,polyendocrinopathies, autoimmune, puberty, delayed, puberty, precocious,renal osteodystrophy, thyroid diseases, thyroid hormone resistancesyndrome, thyroid neoplasms, thyroid nodule, thyroiditis, thyroiditis,autoimmune, thyroiditis, subacute, or Wolfram syndrome.

In one embodiment, “Hypogonadism” is a condition resulting from orcharacterised by abnormally decreased functional activity of the gonads,with retardation of growth and sexual development.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with urogenitaldisease and/or fertility in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and anti-cancer agent, an immunomodulating agent, ananti-infective agent, an agent treating the kidney, gene therapy agent,an agent treating the endocrine system, vitamins, or a combinationthereof. In some embodiments, urogenital diseases and/or fertilitydiseases comprise abortion, spontaneous-adhesions-pelvic, candidiasis,vulvovaginal, depression-postpartum, diabetes, gestational, dyspareunia,dystocia, eclampsia, endometriosis, fetal death, fetal growthretardation, fetal membranes, premature rupture, genital diseases,female, genital neoplasms, female, hydatidiform mole, hyperemesisgravidarum, infertility, ovarian cysts, ovarian torsion, pelvicinflammatory disease, placenta diseases, placental insufficiency,polycystic ovary syndrome, polyhydramnios, postpartum hemorrhage,pregnancy complications, pregnancy, ectopic, pruritus vulvae, puerperaldisorders, puerperal infection, salpingitis, trophoblastic neoplasms,uterine cervix incompetence, uterine inversion, uterine prolapse,vaginal diseases, vulvar diseases, vulvar lichen sclerosis.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with hemic and/orlymphatic disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, ananti-infective agent, an agent treating the liver, an agent treating thekidney, an agent treating a metabolic disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, hemic and/or lymphatic diseases compriseafibrinogenemia, anemia, aplastic anemia, hemolytic anemia, congenitalnonspherocytic anemia, megaloblastic anemia, pernicious anemia, sicklecell anemia, renal anemia, angiolymphoid hyperplasia with eosinophilia,antithrombin III deficiency, Bernard-Soulier syndrome, blood coagulationdisorders, blood platelet disorders, blue rubber bleb nevus syndrome,Chediak-Higashi syndrome, cryoglobulinemia, disseminated intravascularcoagulation, eosinophilia, Erdheim-Chester disease, erythroblastosis,fetal, evans syndrome, factor V deficiency, factor VII deficiency,factor X deficiency, factor XI deficiency, factor XII deficiency,fanconi anemia, giant lymph node hyperplasia, hematologic diseases,hemoglobinopathies, hemoglobinuria, paroxysmal, hemophilia a, hemophiliab, hemorrhagic disease of newborn, histiocytosis, histiocytosis,langerhans-cell, histiocytosis, non-langerhans-cell, job's syndrome,leukopenia, lymphadenitis, lymphangioleiomyomatosis, lymphedema,methemoglobinemia, myelodysplastic syndromes, myelofibrosis, myeloidmetaplasia, myeloproliferative disorders, neutropenia, paraproteinemias,platelet storage pool deficiency, polycythemia vera, protein cdeficiency, protein s deficiency, purpura, thrombocytopenic, purpura,thrombotic thrombocytopenic, RH-isoimmunization, sarcoidosis,sarcoidosis, spherocytosis, splenic rupture, thalassemia,thrombasthenia, thrombocytopenia, Waldenstrom macroglobulinemia, or VonWillebrand disease.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a congenital,hereditary, or neonatal disease in a subject. In one embodiment, themethod comprises administering to a subject a composition comprising acompound of this invention and anti-cancer agent, an immunomodulatingagent, an antidiabetic agent, an agent treating the cardiovascularsystem, an agent treating the gastrointestinal system, an agent treatinga dermatological disorder, an agent treating the central nervous system,an anti-infective agent, an agent treating the liver, an agent treatingthe kidney, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,congenital, hereditary, and neonatal diseases comprise Aicardi syndrome,amniotic band syndrome, anencephaly, Angelman syndrome, ataxiatelangiectasia, Bannayan-Zonana syndrome, Barth syndrome, basal cellnevus syndrome, Beckwith-Wiedemann syndrome, bloom syndrome,branchio-oto-renal syndrome, cat eye syndrome, cerebral gigantism-chargesyndrome, chromosome 16 abnormalities, chromosome 18 abnormalities,chromosome 20 abnormalities, chromosome 22 abnormalities, Costellosyndrome, cri-du-chat syndrome, Currarino syndrome, cystic fibrosis,de-Lange syndrome, distal trisomy 10q, down syndrome, ectodermaldysplasia, fetal alcohol syndrome, fetal diseases, fetofetaltransfusion, fragile x syndrome, Freeman-Sheldon syndrome,gastroschisis, genetic diseases, inborn, hernia, umbilical,holoprosencephaly, incontinentia pigmenti, Ivemark syndrome, Jacobsensyndrome, jaundice, Klinefelter syndrome, Larsen syndrome, Laurence-moonsyndrome, lissencephaly, microcephaly, monosomy 9p, nail-patellasyndrome, neurofibromatoses, neuronal ceroid-lipofuscinosis, Noonansyndrome, ochoa syndrome (urofacial syndrome, hydronephrosis withpeculiar facial expression), oculocerebrorenal syndrome,Pallister-Killian syndrome, Prader-Willi syndrome, proteus syndrome,prune belly syndrome, Rett syndrome, Robinow syndrome, Rubinstein-Taybisyndrome, schizencephaly, situs inversus, Smith-Lemli-Opitz syndrome,Smith-Magenis syndrome, Sturge-Weber syndrome, syphilis, congenital,trichothiodystrophy, triple-x females, trisomy 13 (Patau syndrome),trisomy 9, turner syndrome, twins, conjoined, Usher syndrome,Waardenburg's syndrome, Werner syndrome, or Wolf-Hirschhorn syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a connectivetissue disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and anti-cancer agent, an immunomodulating agent, an agenttreating a dermatological disorder, an anti-infective agent, an agenttreating a metabolic disease, an agent treating a wasting disease, agene therapy agent, an agent treating the endocrine system, vitamins, ora combination thereof. In some embodiments, connective tissue diseasescomprise ankylosing spondylitis, Ehlers-Danlos syndrome,Henoch-Schonlein purpura, Kawasaki disease, Marfan syndrome,polyarteritis nodosa, polymyositis, psoriatic arthritis, reactivearthritis, rheumatoid arthritis, scleroderma, Sjogren's syndrome,xerophthalmia, Still's disease, systemic lupus erythematosus, Takayasudisease, or Wegener's granulomatosis.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a metabolicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and antidiabetic agent, an agent treating the gastrointestinalsystem, an agent treating a dermatological disorder, an agent treatingthe central nervous system, an anti-infective agent, an agent treatingthe liver, an agent treating the kidney, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, metabolic diseases comprise acid-base imbalance,acidosis, alkalosis, alkaptonuria, alpha-mannosidosis, amino acidmetabolism inborn errors, amyloidosis, iron-deficiency anemia, ascorbicacid deficiency, avitaminosis, beriberi, biotinidase deficiency,carbohydrate-deficient glycoprotein syndrome, carnitine disorders,cystinosis, cystinuria, dehydration, fabry disease, fatty acid oxidationdisorders, fucosidosis, galactosemias, Gaucher disease, Gilbert disease,glucosephosphate dehydrogenase deficiency, glutaric acidemia, glycogenstorage disease, Hartnup disease, hemochromatosis, hemosiderosis,hepatolenticular degeneration, histidinemia, homocystinuria,hyperbilirubinemia, hypercalcemia, hyperinsulinism, hyperkalemia,hyperlipidemia, hyperoxaluria, hypervitaminosis A, hypocalcemia,hypoglycemia, hypokalemia, hyponatremia, hypophosphatasia, insulinresistance, iodine deficiency, iron overload, jaundice, chronicidiopathic, leigh disease, lesch-nyhan syndrome, leucine metabolismdisorders, lysosomal storage diseases, magnesium deficiency, maple syrupurine disease, Melas syndrome, Menkes kinky hair syndrome, metabolicdiseases, metabolic syndrome x, metabolism, inborn errors, mitochondrialdiseases, mucolipidoses, mucopolysaccharidoses, Niemann-Pick diseases,obesity, ornithine carbamoyltransferase deficiency disease,osteomalacia, pellagra, peroxisomal disorders, phenylketonurias,porphyria, erythropoietic, porphyrias, progeria, pseudo, gaucherdisease, refsum disease, Reye syndrome, rickets, Sandhoff disease,starvation, tangier disease, Tay-Sachs disease, tetrahydrobiopterindeficiency, trimethylaminuria, tyrosinemias, urea cycle disorders,water-electrolyte imbalance, Wernicke encephalopathy, vitamin Adeficiency, vitamin B12 deficiency, vitamin B deficiency, Wolmandisease, or Zellweger syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a disorder ofenvironmental origin in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating adermatological disorder, an agent treating the central nervous system,an anti-infective agent, an agent treating the liver, an agent treatingthe kidney, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,disorders of environmental origin comprise barotrauma, bites and stings,brain concussion, burns, central cord syndrome, craniocerebral trauma,electric injuries, fractures, bone, frostbite, heat stress disorders,motion sickness, occupational diseases, poisoning, shaken baby syndrome,shoulder injuries, space motion sickness, spinal cord injuries, tickparalysis, or wounds (penetrating and non-penetrating).

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a behaviormechanism in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an agent treating the cardiovascular system, an agenttreating the central nervous system, a gene therapy agent, an agenttreating the endocrine system, vitamins, or a combination thereof. Insome embodiments, behavior mechanisms comprise aggression, attitude todeath, codependency, self-injurious behavior, sexual behavior, or socialbehavior.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a mentaldisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an agent treating the central nervous system, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, mental disorders compriseAsperger syndrome, attention deficit disorder with hyperactivity,autistic disorder, bipolar disorder, borderline personality disorder,capgras syndrome, child behavior disorders, combat disorders,cyclothymic disorder, dependent personality disorder, depressivedisorder, dissociative disorders, dysthymic disorder, eating disorders,firesetting behavior, hypochondriasis, impulse control disorders,Kleine-Levin syndrome, mental disorders, mental disorders diagnosed inchildhood, multiple personality disorder, Munchausen syndrome,Munchhausen syndrome, narcissistic personality disorder, narcolepsy,obsessive-compulsive disorder, paraphilias, phobic disorders, psychoticdisorders, restless legs syndrome, schizophrenia, seasonal affectivedisorder, sexual and gender disorders, sexual dysfunctions,psychological, sleep disorders, somatoform disorders, stress disorders,post-traumatic, substance-related disorders, suicidal behavior, ortrichotillomania.

In one embodiment, “depression” refers to an illness that involves thebody, mood and thoughts that affects the way a person eats, sleeps andthe way one feels about oneself, and thinks about things. The signs andsymptoms of depression include loss of interest in activities, loss ofappetite or overeating, loss of emotional expression, an empty mood,feelings of hopelessness, pessimism, guilt or helplessness, socialwithdrawal, fatigue, sleep disturbances, trouble concentrating,remembering, or making decisions, restlessness, irritability, headaches,digestive disorders or chronic pain.

In one embodiment, “cognition” refers to the process of knowing,specifically the process of being aware, knowing, thinking, learning andjudging. Cognition is related to the fields of psychology, linguistics,computer science, neuroscience, mathematics, ethology and philosophy. Inone embodiment, “mood” refers to a temper or state of the mind Ascontemplated herein, alterations mean any change for the positive ornegative, in cognition and/or mood.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a liver diseasein a subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention andanti-cancer agent, an immunomodulating agent, an agent treating thegastrointestinal system, an anti-infective agent, an agent treating theliver, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments, liverdiseases comprise liver cancer, primary biliary cirrhosis, autoimmunehepatitis, chronic liver disease, cirrhosis of the liver, hepatitis,viral hepatitis (hepatitis a, hepatitis b, chronic hepatitis b,hepatitis c, chronic hepatitis c, hepatitis d, hepatitis e, hepatitisx), liver failure, jaundice, neonatal jaundice, hepatoma, liver cancer,liver abscess, alcoholic liver disease, hemochromatosis, Wilson'sdisease, portal hypertension, primary sclerosing cholangitis,sarcoidosis, tapeworms, alveolar hydatid disease, fascioliasis,schistosomiasis, gaucher disease, Zellweger syndrome, alcoholism, foodpoisoning, pneumococcal pneumonia' or vibrio vulnificus.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a kidney diseasein a subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention andanti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the gastrointestinal system, an anti-infective agent, anagent treating the kidney, an agent treating a metabolic disease, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, kidney diseases compriseacromegaly, acute renal failure (ARF) amyloidosis, autosomal dominantpolycystic kidney disease, kidney stones, kidney cysts, autosomalrecessive polycystic kidney disease, chronic renal failure (CRF),chronic renal disease, coffin-Lowry syndrome, cor pulmonale,cryoglobulinemia, diabetic nephropathy, dyslipidemia, Gaucher disease,glomerulonephritis, goodpasture syndrome, hemolytic uremic syndrome,hepatitis, kidney cancer, kidney stones, leukemia, lipoproteinemia,lupus, multiple myeloma, nephritis, polyartekidney cysts, poststreptococcal glomerulonephritis, glomerulonephritis, kidney pain,preeclampsia, renal tuberculosis, pyelonephritis, renal tubular acidosiskidney disease, streptococcal toxic shock syndrome, thromboembolism,toxoplasmosis, urinary tract infections, vesicoureteral reflux, orwilliams syndrome.

In one embodiment, the kidney disease or disorder is acute, or inanother embodiment, chronic. In one embodiment, clinical indications ofa kidney disease or disorder, wherein the methods of treatment may beuseful include urinary casts, measured GFR, or other markers of renalfunction.

In one embodiment, the methods of this invention are useful in subjectspredisposed to kidney diseases or disorders. In one embodiment, thephrase “predisposed to a kidney disease or disorder” with respect to asubject is synonymous with the phrase “subject at risk”, and includes asubject at risk of acute or chronic renal failure, or at risk of theneed for renal replacement therapy, if the subject is reasonablyexpected to suffer a progressive loss of renal function associated withprogressive loss of functioning nephron units. Whether a particularsubject is at risk is a determination which may routinely be made by oneof ordinary skill in the relevant medical or veterinary art.

In one embodiment, subjects with kidney disease, in particular malesubjects with end-stage renal disease (ESRD) suffer from hypogonadism,with some having concomitant moderate to severe protein-energymalnutrition (PEM), which leads to higher required doses of EPO, lowerQOL scores, and higher mortality. Many have other symptoms associatedwith hypogonadism, including fatigue, lack of apetite, muscle weakness,etc. In some embodiments, the treatment methods of this invention areuseful in treating symptoms associated with hypogonadism, brought aboutin the subject by androgen deficiency in a female (ADIF); androgendeficiency in aging male (ADAM) to include fatigue, depression,decreased libido, erectile dysfunction, decreased cognition, decreasedmood; androgen insufficiency (male or female), androgen deficiency (maleor female).

In one embodiment, diabetic nephropathy is a complication of diabetesthat evolves early, typically before clinical diagnosis of diabetes ismade. The earliest clinical evidence of nephropathy is the appearance oflow but abnormal levels (>30 mg/day or 20 μg/min) of albumin in theurine (microalbuminuria), followed by albuminuria (>300 mg/24 h or 200μg/min) that develops over a period of 10-15 years. In patients withtype 1 diabetes, diabetic hypertension typically becomes manifest earlyon, by the time that patients develop microalbuminuria. Once overtnephropathy occurs, the glomerular filtration rate (GFR) falls over acourse of times, which may be several years, resulting in End StageRenal Disease (ESRD) in diabetic individuals.

Hypertension is another comorbid factor for renal disease. In someembodiments, treatment of renal disease according to the presentinvention may comprise concomitant treatment with a compound of thisinvention and an agent which treats hypertension.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a wastingdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating thecentral nervous system, an agent treating a metabolic disease, an agenttreating a wasting disease, a gene therapy agent, an agent treating theendocrine system, vitamins, or a combination thereof. In someembodiments, wasting diseases comprise muscle injury, bed rest,immobility, nerve injury, neuropathy, diabetic neuropathy, alcoholicneuropathy, subacute combined degeneration of the spinal cord, diabetes,rheumatoid arthritis, motor neurone diseases, Duchenne musculardystrophy, carpal tunnel syndrome, chronic infection, tuberculosis,Addison's disease, adult sma, limb muscle atrophy, alcoholic neuropathy,anorexia, anorexia nervosa, anorexia associated with cachexia, anorexiaassociated with aging, back tumour, dermatomyositis, hip cancer,inclusion body myositis, incontinentia pigmenti, intercostal neuralgia,juvenile rheumatoid arthritis, Legg-Calve-Perthes disease, muscleatrophy, multifocal motor neuropathy, nephrotic syndrome, osteogenesisimperfecta, post-polio syndrome, rib tumor, spinal muscular atrophy,reflex sympathetic dystrophy syndrome, or Tay-Sachs.

A wasting condition or disorder is defined herein as a condition ordisorder that is characterized, at least in part, by an abnormal,progressive loss of body, organ or tissue mass. A wasting condition canoccur as a result of a pathology such as, for example, cancer, or it canbe due to a physiologic or metabolic state, such as disusedeconditioning that can occur, for example, due to prolonged bed rest orwhen a limb is immobilized, such as in a cast, or with the occurrence ofmultiple wounds, including, for example, amputation, as occurs indiabetics, and other conditions, as will be appreciated by one skilledin the art. A wasting condition can also be age associated. The loss ofbody mass that occurs during a wasting condition can be characterized bya loss of total body weight, or a loss of organ weight such as a loss ofbone or muscle mass due to a decrease in tissue protein.

In one embodiment, the terms “muscle wasting” or “muscular wasting”,refer to the progressive loss of muscle mass and/or to the progressiveweakening and degeneration of muscles, including the skeletal orvoluntary muscles which control movement, cardiac muscles which controlthe heart, and smooth muscles. In one embodiment, the muscle wastingcondition or disorder is a chronic muscle wasting condition or disorder.“Chronic muscle wasting” is defined herein as the chronic (i.e.persisting over a long period of time) progressive loss of muscle massand/or to the chronic progressive weakening and degeneration of muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by a muscle protein breakdown or degradation, by muscleprotein catabolism. Protein catabolism occurs because of an unusuallyhigh rate of protein degradation, an unusually low rate of proteinsynthesis, or a combination of both. Protein catabolism or depletion,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. The term “catabolism” has its commonly known meaning in theart, specifically an energy burning form of metabolism.

Muscle wasting can occur as a result of pathology, disease, condition ordisorders, including disorders for treatment via the methods of thisinvention, such as, for example, end stage renal failure.

In some embodiments, the present invention provides a method forprevention of statin induced rhabdomyolysis. In some embodiments, thepresent invention provides a method for prevention of statin inducedrhabdomyolysis, organ failure or insufficiency. In some embodiments, thepresent invention provides a method for prevention of statin inducedkidney or liver failure or insufficiency. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and a statin.

In one embodiment, the wasting disease is cachexia or involuntary weightloss in a subject. In another embodiment, the present invention providesa method of treating, preventing, inhibiting, reducing or suppressingmuscle wasting in a subject suffering from a kidney disease. In oneembodiment, the present invention provides a method of treating,preventing, inhibiting, reducing or suppressing protein catabolism in asubject suffering from a kidney disease or disorder,

Cachexia is weakness and a loss of weight caused by a disease or as aside effect of illness. Long term hospitalization due to illness orinjury, or disuse deconditioning that occurs, for example, when a limbis immobilized, can also lead to muscle wasting. Studies have shown thatin patients suffering injuries, chronic illnesses, burns, trauma orcancer, who are hospitalized for long periods of time, there is along-lasting unilateral muscle wasting, with a consequent decrease inbody mass. Nervous system injury, for example, spinal cord injury, asdescribed further herein, may be a contributory factor, as well.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a wastingdiseases or disorders in a subject. In another embodiment, the wastingdiseases and disorders include inter-alia: a) acquired immunodeficiencysyndrome (AIDS) wasting; b) wasting associated with bed rest; c)bulimia,

and/or wasting associated with bulimia; c) cachexia; d) cancer cachexia;e) HIV wasting; f) reduce cachexia and protein loss due to prolongedcritical illness, pulmonary dysfunction, ventilator dependency, aging,AIDS, trauma, surgery, congestive heart failure, cardiac myopathy,burns, cancer, chronic obstructive pulmonary disease (COPD), eatingdisorders such bulimia, anorexia nervosa, loss of appetite, starvation,and/or depression.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with invalid statesin a subject. In one embodiment, the invalid state is post-poliosyndrome. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention and animmunomodulating agent, an antidiabetic agent, an agent treating thecardiovascular system, an agent treating the gastrointestinal system, anagent treating the central nervous system, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a hypogonadalstate in a subject. In one embodiment, the present invention provides amethod for treating, reducing the incidence, delaying the onset orprogression, or reducing and/or abrogating the symptoms associated witha pharmacotherapy induced hypogonadal state in a subject. In someembodiments, hypogonadism is caused by treatments which alter thesecretion of hormones from the sex glands in both women and men. In someembodiments, hypogonadism may be “primary” or “central”. In primaryhypogonadism, the ovaries or testes themselves do not function properly.In some embodiments, hypogonadism may be induced by surgery, radiation,genetic and developmental disorders, liver and kidney disease,infection, or certain autoimmune disorders. In some embodiments,menopause is a form of hypogonadism. Menopause may cause, in someembodiments, amenorrhea, hot flashes, vaginal dryness, or irritabilitydue to woman's estrogen levels fall. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and an anti-cancer agent, an immunomodulating agent,an antidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating thecentral nervous system, an agent treating a metabolic disease, an agenttreating a wasting disease, a gene therapy agent, an agent treating theendocrine system, an agent treating a dermatological disorder, ananti-infective agent, an agent treating the liver, an agent treating thekidney, vitamins, or a combination thereof.

In another embodiment, the invention provides a contraceptive, and/or amethod of use thereof, the contraceptive comprising a compositioncomprising a NRBA, which in one embodiment is a SERM of formula (I)-(XI)or its prodrug, ester, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof. In oneembodiment, the invention provides a method for providing post-coitalcontraception by administering the composition comprising a NRBA, whichin one embodiment is a SERM of formula (I)-(XI) or its prodrug, ester,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,hydrate or any combination thereof.

In one embodiment this invention provides a method of treating a subjectsuffering from post menopausal conditions, said method comprising thestep of administering to said subject a NRBA, which in one embodiment isa SERM and/or its pharmaceutically acceptable salt, hydrate, N-oxide, orany combination thereof.

In another embodiment this invention provides a method of suppressing,inhibiting or reducing the risk of post menopausal conditions, saidmethod comprising the step of administering to said subject a NRBA,which in one embodiment is a SERMs and/or its pharmaceuticallyacceptable salt, hydrate, N-oxide, or any combination thereof.

In another embodiment, the invention provides a method of treating,preventing, suppressing, inhibiting, or reducing the incidence of hotflashes, gynecomastia, and/or hair loss in female subjects, or inanother embodiment, in male human subjects. In one embodiment, inventionprovides a method of treating, preventing, suppressing, inhibiting, orreducing the incidence of hot flashes, gynecomastia, and/or hair loss ina male subject having prostate cancer, comprising administering a NRBA,which in one embodiment is a SERM of formula (I)-(XI) or its prodrug,ester, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, hydrate or any combination thereof, or a composition comprisingthe same, thereby treating, preventing, suppressing, inhibiting, orreducing the incidence of hot flashes, gynecomastia, and/or hair loss insaid male human subjects.

In one embodiment, the term “hot flashes” refers to the following:sudden feeling of heat in the upper part or all of the body, face andneck flush, red blotches appearing on the chest, back and arms, heavysweating, cold shivering, etc.

It is to be understood that any sex hormone-dependent disease, disorderor condition may be treated via the methods of this invention, using theSERMs/compositions of this invention.

In one embodiment, hot flashes can be treated with any SERM, which has astructure characterized by any of the formulas, as described herein. Inone embodiment, hot flashes may be treated, prevented, alleviated withthe following SERMs chosen based on their pharmacologic activity asdemonstrated in receptor binding studies, estrogen receptortransactivation, in vitro studies of osteoblast and osteoclast activity,and in vivo studies

Hot flash is mediated by both ER-α and ER-β. In some embodiments, toovercome this, tissue selective agonists of both the isoforms can beused. In some embodiments, side effects associated with some ER-αagonists such as thromboembolism, mammary carcinogenesis and uterinecancer, may be avoided via selection of specific ER-βagonists for thisindication.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with osteopenic statein a subject. In one embodiment, the present invention provides a methodfor treating, reducing the incidence, delaying the onset or progression,or reducing and/or abrogating the symptoms associated with apharmacotherapy induced osteopenic state in a subject. In someembodiments, osteopenia is a mild thinning of the bone mass. In someembodiments, osteopenia is a precursor to osteoporosis. In someembodiments osteopenia is defined as a bone density between one standarddeviation (SD) and 2.5 SD below the bone density of a normal youngadult. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention and ananti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins, or acombination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a sarcopenicstate in a subject. In one embodiment, the present invention provides amethod for treating, reducing the incidence, delaying the onset orprogression, or reducing and/or abrogating the symptoms associated witha pharmacotherapy induced sarcopenic state in a subject. In someembodiments, sarcopenia is a significant loss of muscle mass. In oneembodiment, sarcopenia definition is having a lean body mass less thantwo standard deviation below the mean for normal young adults. In someembodiments, sarcopenia is caused by genetic factors, alteredcirculation, decrease in the capillary:muscle fiber ratio, altered motorneurons, denervation, deterioration of motor end plates, selectivereinnervation of Type I fibers, inflammatory responses causing muscledamage, reduced exercise, malnutrition, low dietary protein intake,vitamin D deficiency, age-related decline in vitamin D, oxidativestress, muscle mitochondrial mutations, changes in specific types ofmuscle fibers, decline in muscle protein, disabling disease, strokes,Alzheimer's disease, Parkinson's disease, osteoporosis, atherosclerosis,diabetes mellitus, hyperinsulinemia, renal failure, or hypogonadism. Inone embodiment, the method comprises administering to a subject acomposition comprising a SARM compound and an anti-cancer agent, animmunomodulating agent, an antidiabetic agent, an agent treating thecardiovascular system, an agent treating the gastrointestinal system, anagent treating the central nervous system, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, an agent treating a dermatologicaldisorder, an anti-infective agent, an agent treating the liver, an agenttreating the kidney, vitamins, or a combination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a combination ofdiseases and/or disorders in a subject as described hereinabove. In oneembodiment, the method comprises administering to a subject acomposition comprising a compound of this invention and an anti-canceragent, an immunomodulating agent, an antidiabetic agent, an agenttreating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins, or acombination thereof.

It is to be understood that any method of this invention, as hereindescribed, encompasses the administration of a compound as hereindescribed, or a composition comprising the same, to the subject, inorder to treat the indicated disease, disorder or condition. The methodsas herein described each and/or all may further comprise administrationof an additional therapeutic agent as herein described, and as will beappreciated by one skilled in the art.

In some embodiments, the present invention provides a method forenhanced production such as milk, sperm, or egg. In some embodiments,the present invention provides a method for enhanced production of leanmeats or eggs. In some embodiments, the present invention provides amethod for increased productivity of feeds or stud livestock, forexample, increased sperm count, improved morphology of sperm, etc. Insome embodiments, the present invention provides a method for expandingthe productive life of farm animals, for example, egg-laying hens,milk-producing cows, etc, and/or enhanced herd health, for example,improved immune clearance, stronger animals.

In one embodiment, the method comprises administering to a subject acomposition comprising a compound of this invention and an anti-canceragent, an immunomodulating agent, an antidiabetic agent, an agenttreating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins,nutritional additives, hormones, each and/or all as herein described, orany other therapeutic agent as herein described, or a combinationthereof.

In another embodiment, this invention provides methods of treatment ofcystic fibrosis and induced hypogonadal states as a result of the same,epilepsy and induced hypogonadal and/or hypermetabolic states as aresult of the same, hereditary angioedema, lupus erythematosus anddecreased BMD as a result of the same, alcohol and smoking inducedosteoporosis, in a subject the methods comprising administering acompound as herein described to the subject.

In another embodiment, this invention provides methods of treatment ofpolio and post-polio syndrome and other invalid states, statin inducedrhabdomyolysis, statin-induced muscle weakness, statin-induced organfailure or insufficiency, in a subject, the methods comprising theadministration of a compound as herein described, optionally with astatin, as appropriate, as will be appreciated by one skilled in theart, and/or with any therapeutic agent.

In another embodiment, this invention provides a method of treatingOpioid Induced Androgen Deficiency (OPIAD), the method comprisingadministering to the subject a compound as herein described, andoptionally opiates, opioids, narcotics, etc. methadone, long-actingopiates/opioids such as Kadian, extended release morphines, allopiates/opioids/narcotics agents approved by FDA, opiates/opioids usedin treatment of heroin addiction, opiates/opioids used in the treatmentof chronic pain of malignancy, opiates/opioids used in the treatmentnon-malignant of chronic pain syndromes.

In another embodiment, this invention provides a method of treating anervous system disease, disorder or condition, the method comprisingadministering to the subject a compound as herein described, andoptionally anti-psychotics, such as, for example, zotepine, haloperidol,amisulpride, risperidone, other D2 dopamine receptor antagonists;anti-epileptics, such as valproic acid, carbamazepine, oxcarbamazepine,etc. or combinations thereof.

In another embodiment, this invention provides a method of treating ahormone dependent disease, disorder or condition, the method comprisingadministering to the subject a compound as herein described, andoptionally chemotherapeutics agents and therapies (methotrexate,cyclophosphamide, ifosfamide, adriamycin, doxorubicin, glucocorticoids,cyclosporine, L-thyroxine, SERMs, AI, fulvestrant, GnRH agents, ADT,discontinuation of hormone replacement therapy, cranial irradiation,peripheral irradiation, etc.; prolactinemia-inducingpharmacotherapeutics (serotonergic antidepressants acting through 5HT2receptors, selective serotonin reuptake inhibitors, monoamine oxidaseinhibitors, tricyclic antidepressants, antihypertensives such asmethyldopa, reserpine, clonidine, and verapamil; antidopaminergicanti-emetics such as metoclopramide, H2 receptor antagonists such ascimetidine and ranitidine, estrogens, amphetamines, AR partialantagonists (ketoconazole, spironolactone, eplerenone)

In another embodiment, the compounds of this invention and compositionsas described herein are useful in promoting or speeding recoveryfollowing a surgical procedure.

In one embodiment, the present invention provides a use of a compound asdescribed herein for reducing a fat mass in a subject. In anotherembodiment the invention provides such methods for use of the compoundas described herein or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, or a composition comprising the same.

In another embodiment, this invention provides for the use of a compoundas described herein or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, or a composition comprising the same, in treating abdominal fataccumulation; improving body composition; lowering body fat content;lowering fat mass; improving blood lipid profile, increasing musclemass/strength/function; increasing bone mass/BMD/strength/function;lowering body fat; congenital hyperinsulinemia; cushing's disease(hypercortisolemia); obesity or diabetes associated with a metabolicsyndrome in a subject.

In another embodiment, the subject has a hormonal imbalance, disorder,or disease. In another embodiment the subject has menopause.

In one embodiment, the present invention provides a use of a compound asdescribed herein for increasing a lean mass in a subject. In anotherembodiment such use comprises administration of a compound as describedherein or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof.

In one embodiment the subject has a hormonal imbalance, disorder, ordisease. In another embodiment the subject has menopause.

In one embodiment, the compounds as herein described alter the levels ofleptin in a subject. In another embodiment, the compounds as hereindescribed decrease the levels of leptin. In another embodiment, thecompounds as herein described increase the levels of leptin in asubject. Leptin is known to have an effect on appetite on weight loss inobese mice, and thus has been implicated in obesity.

The compounds as herein described, in one embodiment, affectcirculating, or in another embodiment, tissue levels of leptin. In oneembodiment, the term ‘level's of leptin’ refers to the serum level ofleptin. As contemplated herein, the compounds of the present inventionhave an effect on leptin in-vitro and in-vivo. Leptin levels can bemeasured by methods known to one skilled in the art, for example bycommercially available ELISA kits. In addition, Leptin levels may bedetermined in in-vitro assays, or in in-vivo assays, by any method knownto a person skilled in the art.

Since leptin is implicated in controlling appetite, weight loss, foodintake, and energy expenditure, modulating and/or controlling the levelsof leptin is a useful therapeutic approach in treating preventing,inhibiting or reducing the incidence of obesity in subjects sufferingfrom obesity. Modulating the level of leptin can result in a loss ofappetite, a reduction of food intake, and an increase in energyexpenditure in the subject, and thus may contribute to the control andtreatment of obesity.

The term “obesity” is defined, in one embodiment, as an increase in bodyweight beyond the limitation of skeletal and physical requirement, asthe result of excessive accumulation of fat in the body.

The term “obesity-associated metabolic disorder” refers, in oneembodiment, to a disorder which results from, is a consequence of, isexacerbated by or is secondary to obesity. Non-limiting examples of sucha disorder are osteoarthritis, Type II diabetes mellitus, increasedblood pressure, stroke, and heart disease.

Cholesterol, triacylglycerol and other lipids are transported in bodyfluids by lipoproteins which may be classified according to theirdensity, for example, the very low density lipoproteins (VLDL),intermediate density lipoproteins (IDL), low density lipoproteins (LDL)and high density lipoproteins (HDL).

It has been shown that high levels of LDL-Cholesterol in the bloodcorrelate with atherosclerosis which is a progressive diseasecharacterized in part by sedimentation of lipids in inner walls ofarteries, particularly of coronary arteries. It has also been shown thata high blood level of LDL-Cholesterol correlates with coronary heartdisease. Also, a negative correlation exists between blood levels of HDLcholesterol and coronary heart disease.

The level of total cholesterol in blood, which is the sum ofHDL-Cholesterol, LDL-Cholesterol, VLDL-Cholesterol andchylomicron-Cholesterol, is not necessarily predictive of the risk ofcoronary heart disease and atherosclerosis.

The correlation between atherosclerosis and LDL cholesterol levels,however, is much higher than a similar correlation betweenatherosclerosis and total serum cholesterol levels.

In one embodiment, this invention provides methods of use of thecompounds as herein described for improving the lipid profile and/orreducing the circulating lipid levels in a subject. In some embodiments,according to this aspect of the invention, the subject suffers from oneor more conditions selected from the group consisting of:atherosclerosis and its associated diseases, premature aging,Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis,peripheral vascular insufficiency, renal disease, and hyperglycemia, andthe invention provides for the administration of a compound orcomposition comprising the same, as herein described, which in someembodiments positively affects a lipid profile in the subject, which isone means by which the method is useful in treating the indicateddiseases, disorders and conditions.

In one embodiment the invention provides for the treatment ofatherosclerosis and its associated diseases, such as for example,cardiovascular disorders, cerebrovascular disorders, peripheral vasculardisorders, intestinal vascular disorders, or combinations thereof.

In one embodiment cardiovascular disorders comprise of hypertension(HTN), coronary artery disease (CAD) or myocardial perfusion. In anotherembodiment this invention provides methods of use of the SARM compoundsas herein described for promoting aortic smooth muscle cellproliferation. In another embodiment this invention provides methods ofuse of the compounds as herein described for treating arteriosclerosis.In another embodiment this invention provides methods of use of thecompounds as herein described for lowering blood pressure. In anotherembodiment this invention provides methods of use of the compounds asherein described for treating cardiac diseases and disorders comprisingcardiomyopathy, cardiac dysfunctions such as, myocardial infarction,cardiac hypertrophy and cognitive heart failure. In another embodimentthis invention provides methods of use of the compounds as hereindescribed for cardioprotection comprising cardioprotection in insulinresistance; treating diabetes type I and II, metabolic syndrome,syndrome X and/or high blood pressure.

In one embodiment, the invention provides a method of treating,preventing, reducing the risk of mortality from cardiovascular and/orcerebrovascular disease in a subject, comprising administering acompound of this invention or its prodrug, ester, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, hydrate or anycombination thereof, or a pharmaceutical composition comprising thesame.

In one embodiment, compounds of this invention reduce LDL and totalcholesterol levels. In another embodiment the compound of this inventionreduces LDL and total cholesterol levels in a subject.

In another embodiment, compounds of this invention are co-administeredwith HDL-elevating agents. In another embodiment, a compound of thisinvention is co-administered with an HDL-elevating agents. In anotherembodiment, HDL-elevating agents include niacin. In another embodimentthe HDL-elevating agents include fibrates including gemfibrozil (Lopid),thiourea based gemfibrozil analogues, and fenofibrate (TriCor). Inanother embodiment, HDL-elevating agents include statins. In anotherembodiment, HDL-elevating agents include1-hydroxyalkyl-3-phenylthiourea, and analogs thereof.

In one embodiment, this invention provides a method of reducingcirculating lipid levels in a subject, said method comprisingadministering a compound of this invention or its pharmaceuticallyacceptable salt, hydrate, N-oxide, or any combination thereof, or acomposition comprising the same. In one embodiment, the subject suffersfrom atherosclerosis and its associated diseases, premature aging,Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis,peripheral vascular insufficiency, renal disease, hyperglycemia, or anycombination thereof.

In one embodiment, this invention provides a method of treatingatherosclerosis and its associated diseases, such as, for example,cardiovascular disorders, cerebrovascular disorders, peripheral vasculardisorders, or intestinal vascular disorders in a subject, the methodcomprising the step of administering to the subject compound of thisinvention or its pharmaceutically acceptable salt, hydrate, N-oxide, orany combination thereof, or a composition comprising the same. Themethod may further comprise co-administration, subsequent or prioradministration with an agent or agents, which are known to be useful intreating cardiovascular disorders, cerebrovascular disorders, peripheralvascular disorders, or intestinal vascular disorders.

Cardiovascular cells, as well as reproductive tissues, bone, liver, andbrain, express both of the known estrogen receptors, estrogen receptor-α(ER-α) and estrogen receptor-β (ER-β). These receptors are importanttargets for endogenous estrogen, estrogen replacement therapy (ERT), andpharmacological estrogen agonists. Estrogen—estrogen receptor complexesserve as transcription factors that promote gene expression with a widerange of vascular effects, including regulation of vasomotor tone andresponse to injury, which may be protective against development ofatherosclerosis and ischemic diseases. Estrogen receptors in othertissues, such as the liver, may mediate both beneficial effects (e.g.,changes in apoprotein gene expression that improve lipid profiles) andadverse effects (e.g., increases in gene expression of coagulationproteins and/or decreases in fibrinolytic proteins). Two generalestrogen-mediated vascular effects are recognized. Rapid, transientvasodilation occurs within a few minutes after estrogen exposure,independently of changes in gene expression. Longer-term effects ofestrogen on the vasculature, such as those related to limiting thedevelopment of atherosclerotic lesions or vascular injury, occur overhours to days after estrogen treatment and have as their hallmarkalterations in vascular gene expression. Progesterone and other hormonalreceptors are also expressed in the vasculature.

In another embodiment, the invention provides a method of improving alipid profile in a subject, comprising administering a NRBA, which inone embodiment is a SERM of formula (I)-(XI) or its prodrug, ester,analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,hydrate or any combination thereof, or a composition comprising thesame, thereby improving the lipid profile in said subject. In someembodiments ER-β agonists are useful in improving a lipid profile in asubject In another embodiment, ER-β agonist of this invention iscompound 3a, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3d, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3e, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3l,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3g, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 3j, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3i, listed inTable 1, or any combination thereof. In another embodiment, ER-β agonistof this invention is compound 4a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 4h, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 4u, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10o, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10f, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10l, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10w, listed inTable 1, or any combination thereof.

In some embodiments, the phrase “improving a lipid profile” may refer tolowering pathogenic circulating lipid levels, lowering plaque formationin vasculature, altering circulating HDL/LDL ratios, ratios reducing theratio of LDL levels to HDL levels, lowering circulating cholesterollevels, preventing lipid accumulation in vasculature, or any combinationthereof, or other therapeutic effects related thereto, as will beappreciated by one skilled in the art.

In one embodiment, the invention provides a method of treating,preventing, reducing the risk of mortality from vasculature diseasedisorder or condition in a subject, comprising administering a NRBA,which in one embodiment is a SERM, of formula (I)-(XI) or its prodrug,ester, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, hydrate or any combination thereof, or a composition comprisingthe same.

In one embodiment, vasculature disease disorder or condition maycomprise, inter alia, aortic smooth cell proliferation, restenosis,repurfusion injury, vascular smooth muscle cell proliferation orvasospasm.

In one embodiment, the invention provides a method of treating,preventing, reducing the risk of mortality from cardiovascular and/orcerebrovascular disease in a subject, comprising administering a NRBA,which in one embodiment is a SERM, of formula (I)-(XI) or its prodrug,ester, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, hydrate or any combination thereof, or a composition comprisingthe same. In some embodiments ER-β agonists are useful in treating,preventing, reducing the risk of mortality from cardiovascular and/orcerebrovascular disease in a subject. In another embodiment, ER-βagonist of this invention is compound 3a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 3e, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3l, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3g, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3j,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3i, listed in Table 1, or any combination thereof. Inanother embodiment, ER-β agonist of this invention is compound 4a,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 4h, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 4u, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10o, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10d, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10f, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10l, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10w, listed in Table 1, or any combination thereof.

In one embodiment, cardiovascular disease comprises, inter alia,atherosclerosis of the coronary arteries, angina pectoris, andmyocardial infarction. In one embodiment, cerebrovascular diseasecomprises, inter alia, atherosclerosis of the intracranial orextracranial arteries, stroke, syncope, and transient ischemic attacks.

In one embodiment, this invention provides a method of improving thedexterity and movement in a subject, for example, by treating arthritisin the subject.

The term “arthritis” refers, in another embodiment, to anon-inflammatory degenerative joint disease occurring chiefly in olderpeople, characterized by degeneration of the articular cartilage,hypertrophy of bones and the margins, changes in the synovial membrane,etc. It is accompanied, in other embodiments, by pain and stiffness,particularly after prolonged activity.

The term “diabetes”, in one embodiment, refers to a relative or absolutelack of insulin leading to uncontrolled carbohydrate metabolism. Mostpatients can be clinically classified as having either insulin-dependentdiabetes mellitus (IDDM or Type-I diabetes) or non-insulin-dependentdiabetes mellitus (NIDDM or Type-II diabetes).

The term “increased blood pressure” or “hypertension” refers, in otherembodiments, to a repeatedly high blood pressure above 140 over 90 mmHg.Chronically-elevated blood pressure can cause blood vessel changes inthe back of the eye, thickening of the heart muscle, kidney failure, andbrain damage.

The term “stroke” refers, in other embodiments, to damage to nerve cellsin the brain due to insufficient blood supply often caused by a burstingblood vessel or a blood clot. The term “heart disease”, in otherembodiments, refers to a malfunction in the heart normal function andactivity, including heart failure.

In addition, androgens have recently been shown to be involved incommitment of mesenchymal pluripotent cells into myogenic lineage and toblock differentiation into adipogenic lineage (Singh et al.,Endocrinology, 2003, Jul. 24). Accordingly, the compounds can be usefulin methods of blocking adipogenesis, and/or altering stem celldifferentiation, as described herein.

In another embodiment, this invention relates to a method of promoting,increasing or facilitating weight loss in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to promote,increase or facilitate weight loss in the subject.

In another embodiment, this invention relates to a method of decreasing,suppressing, inhibiting or reducing appetite of a subject, comprisingthe step of administering to the subject a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal, or any combination thereof, in an amount effectiveto decrease, suppress, inhibit or reduce the appetite of the subject.

In another embodiment, this invention relates to a method of alteringthe body composition of a subject, comprising the step of administeringto the subject a compound as herein described and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal,or any combination thereof, in an amount effective to alter the bodycomposition of the subject. In one embodiment, altering the bodycomposition comprises altering the lean body mass, the fat free bodymass of the subject, or a combination thereof.

In another embodiment, this invention relates to a method of alteringlean body mass or fat free body mass of a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to alter thelean body mass or fat free body mass of the subject.

In another embodiment, this invention relates to a method of convertingfat to lean muscle in a subject, comprising the step of administering tothe subject a compound as herein described and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal,or any combination thereof, in an amount effective to convert fat tolean muscle in the subject.

In another embodiment, this invention relates to a method of treating anobesity-associated metabolic disorder in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to treat theobesity-associated metabolic disorder in the subject.

In another embodiment, this invention relates to a method of preventing,suppressing, inhibiting or reducing an obesity-associated metabolicdisorder in a subject, comprising the step of administering to thesubject a compound as herein described and/or its analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, crystal, or anycombination thereof, in an amount effective to prevent, suppress,inhibit or reduce the obesity-associated metabolic disorder in thesubject.

In one embodiment, the obesity-associated metabolic disorder ishypertension. In another embodiment, the disorder is osteoarthritis. Inanother embodiment, the disorder is Type II diabetes mellitus. Inanother embodiment, the disorder is increased blood pressure. In anotherembodiment, the disorder is stroke. In another embodiment, the disorderis heart disease.

In another embodiment, this invention relates to a method of decreasing,suppressing, inhibiting or reducing adipogenesis in a subject,comprising the step of administering to the subject a compound as hereindescribed and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal, or any combination thereof.

In another embodiment, this invention relates to a method of alteringstem cell differentiation in a subject, comprising the step ofadministering to the subject a compound as herein described and/or itsanalog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to alterstem cell differentiation in the subject.

In one embodiment, the compounds as herein described are useful in a)treating, preventing, suppressing, inhibiting, or reducing obesity; b)promoting, increasing or facilitating weight loss; c) decreasing,suppressing, inhibiting or reducing appetite; d) altering the bodycomposition; e) altering lean body mass or fat free body mass;converting fat to lean muscle; f) g) treating, preventing, suppressing,inhibiting, or reducing an obesity-associated metabolic disorder, forexample hypertension, osteoarthritis, diabetes mellitus, MODY, increasedblood pressure, stroke, or heart disease; h) decreasing, suppressing,inhibiting or reducing adipogenesis; i) altering stem celldifferentiation; and/or j) altering the level of leptin.

In one embodiment, the compounds as herein described find utility intreating or halting the progression of, or treating symptoms ofdiabetes. In another embodiment, the compounds as herein described areuseful in treating co-morbidities related to diabetes. These conditionsinclude: hypertension (HTN), cerebrovascular disease, atheroscleroticcoronary artery disease, macular degeneration, diabetic retinopathy (eyedisease) and blindness, cataracts-systemic inflammation (characterizedby elevation of inflammatory markers such as erythrocyte sedimentationrate or C-reactive protein), birth defects, pregnancy related diabetes,pre-eclampsia and hypertension in pregnancy, kidney disease (renalinsufficiency, renal failure etc.), nerve disease (diabetic neuropathy),superficial and systemic fungal infections, congestive heart failure,gout/hyperuricemia, obesity, hypertriglyceridemia, hypercholesterolemia,fatty liver disease (non-alcoholic steatohepatitis, or NASH), anddiabetes-related skin diseases such as Necrobiosis LipoidicaDiabeticorum (NLD), Blisters of diabetes (Bullosis Diabeticorum),Eruptive Xanthomatosis, Digital Sclerosis, Disseminated GranulomaAnnulare, and Acanthosis Nigricans.

In one embodiment this invention provides a method of treating,suppressing, inhibiting or reducing the incidence of (a) diabetes typeI; (b) diabetes type II; (c) glucose intolerance; (d) hyperinsulinemia;(e) insulin resistance (f) nephropathy; (g) diabetic neuropathy; (h)diabetic retinopathy (i) fatty liver conditions (j) MODY and (k)cardiovascular disease in a human subject, comprising the step ofadministering to said subject a compound of this invention.

In some embodiments, the compounds as herein described and/orcompositions comprising the same may be used for applications in, ortreating diseases or conditions associated with a subject havingdiabetes. In one embodiment, the subject for whom treatment is soughtvia the methods of this invention is one with diabetic I. Type Idiabetes is characterized by autoimmune destruction of pancreaticbeta-cells. Markers of immune destruction of the beta-cell are presentat the time of diagnosis in 90% of individuals and include antibodies tothe islet cell (ICAs), to glutamic acid decarboxylase (GAD), and toinsulin (IAAs). While this form of diabetes usually occurs in childrenand adolescents, it can occur at any age. Younger individuals typicallyhave a rapid rate of beta-cell destruction and present withketoacidosis, while adults often maintain sufficient insulin secretionto prevent ketoacidosis for many years. Eventually, all type I diabeticpatients require insulin therapy to maintain normglycemia.

In one embodiment, this invention provides a method of treating diabetestype II. Type II diabetes is characterized by insulin resistance and atsome stage in pathogenesis of the disease, a relative deficiency ofinsulin secretion. In absolute terms, the plasma insulin concentration(both fasting and meal-stimulated) usually is increased, although“relative” to the severity of insulin resistance, the plasma insulinconcentration is insufficient to maintain normal glucose homeostasis.With time, however, there is progressive beta cell failure and absoluteinsulin deficiency ensues. Most individuals with type II diabetesexhibit intra abdominal (visceral) obesity, fatty liver, which isclosely related to the presence of insulin resistance. The patient'sliver becomes insulin resistant and glycogen breakdown is uncontrolledand the result is increased and unphysiological glucose delivery to thebloodstream. The liver generated cholesterol and VLDL particles is alsouncontrolled. In addition, hypertension, dyslipidemia (high triglycerideand low HDL-cholesterol levels; postprandial hyperlipemia), and elevatedPAI-1 levels often are present in these individuals. This clustering ofabnormalities is referred to as the “insulin resistance syndrome”, orthe “metabolic syndrome” or obesity related disorders. Because of theseabnormalities, patients with type II diabetes are at increased risk ofdeveloping macrovascular complications such as myocardial infarction andstroke.

In one embodiment, this invention provides a method of treating diabeticnephropathy. Diabetic nephropathy is a complication of diabetes thatevolves early, typically before clinical diagnosis of diabetes is made.The earliest clinical evidence of nephropathy is the appearance of lowbut abnormal levels (>30 mg/day or 20 μg/min) of albumin in the urine(microalbuminuria), followed by albuminuria (>300 mg/24 h or 200 μg/min)that develops over a period of 10-15 years. In patients with type 1diabetes, diabetic hypertension typically becomes manifest early on, bythe time that patients develop microalbuminuria. Once overt nephropathyoccurs, the glomerular filtration rate (GFR) falls over a course oftimes, which may be several years, resulting in End Stage Renal Disease(ESRD) in diabetic individuals.

In one embodiment, this invention provides a method of treating diabeticneuropathy. Diabetic neuropathy is a family of nerve disorders caused bydiabetes. Diabetic neuropathies cause numbness and sometimes pain andweakness in the hands, arms, feet, and legs. Neurologic problems indiabetes may occur in every organ system, including the digestive tract,heart, and genitalia. Diabetic neuropathies are classified asperipheral, autonomic, proximal, and focal. Peripheral neuropathy causespain or loss of feeling in the toes, feet, legs, hands, and arms.Autonomic neuropathy causes changes in digestion, bowel and bladderfunction, sexual response, and perspiration and can also affect thenerves that serve the heart and control blood pressure. Proximalneuropathy causes pain in the thighs, hips, or buttocks and leads toweakness in the legs. Focal neuropathy results in the sudden weakness ofone nerve, or a group of nerves, causing muscle weakness or pain. Anynerve in the body may be affected.

In one embodiment, this invention provides a method of treating diabeticretinopathy. The effect of diabetes on the eye is called diabeticretinopathy. Patients with diabetes are more likely to develop eyeproblems such as cataracts and glaucoma. The affect of diabeticretinopathy on vision varies widely, depending on the stage of thedisease. Some common symptoms of diabetic retinopathy are blurred vision(this is often linked to blood sugar levels), floaters and flashes andsudden loss of vision.

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with glucose intolerance. Glucoseintolerance is a pre-diabetic state in which the blood glucose is higherthan normal but not high enough to warrant the diagnosis of diabetes.

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with hyperinsulinemia. Hyperinsulinemiais a sign of an underlying problem that is causing the pancreas tosecrete excessive amounts of insulin. The most common cause ofhyperinsulinemia is insulin resistance, a condition in which your bodyis resistant to the effects of insulin and the pancreas tries tocompensate by making more insulin. hyperinsulinemia is associated withtype II diabetes

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with insulin resistance. Insulinresistance is a condition in which normal amounts of insulin areinadequate to produce a normal insulin response from fat, muscle andliver cells. Insulin resistance in fat cells results in hydrolysis ofstored triglycerides, which elevates free fatty acids in the bloodplasma. Insulin resistance in muscle reduces glucose uptake whereasinsulin resistance in liver reduces glucose storage, with both effectsserving to elevate blood glucose. High plasma levels of insulin andglucose due to insulin resistance often leads to the metabolic syndromeand type II diabetes.

Diabetes and the liver obesity is typically associated with elevatedlevels of free fatty acid (FFAs) that promote lipid accumulation andinsulin resistance in target tissues, i.e. reduced action of insulinprimarily in skeletal muscle and liver. A prominent role of insulin isto reduce glucose output from the liver. FFAs stimulate hepaticgluconeogenesis which per se does not lead to increased hepatic glucoseoutput as long as it is paralleled by a decrease in hepaticglycogenolysis, a compensatory process referred to as “hepaticautoregulation”. FFAs stimulate insulin secretion and insulin blocksglycogenolysis in part by inhibiting secretion of glucagon, an inducerof glycogenolysis. However, long-term elevated levels of FFAs leads tohepatic insulin resistance and thus breakdown of hepatic autoregulation,resulting in increased hepatic glucose production and development oftype II diabetes. Fatty liver and hepatic insulin resistance is a majordriving force behind hyperglycemia and type II diabetes.

In one embodiment, this invention provides methods that inhibit(improve) the fatty liver, resulting in that the insulin resistance inthe liver is inhibited (improved) and thereby solving the basic problemin type II diabetes.

In another embodiment, the diabetes is a type I diabetes. In anotherembodiment, the diabetes is a type II diabetes.

In one embodiment, this invention provides a method of treatingsuppressing, inhibiting or reducing the incidence of diabetes is a humansubject, comprising the step of administering to said subject a compoundof this invention or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, or any combination thereof.

In another embodiment, the diabetes is a Type I diabetes. In anotherembodiment, the diabetes is a type II diabetes.

In one embodiment, this invention provides a method of treating a humansubject having glucose intolerance, comprising the step of administeringto said subject compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treatinghyperinsulinemia in a human subject, comprising the step ofadministering to said subject a compound of this invention or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treating insulinresistance in a human subject, comprising the step of administering tosaid subject the compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treating diabeticnephropathy in a human subject, comprising the step of administering tosaid subject a compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treating diabeticneuropathy in a human subject, comprising the step of administering tosaid subject compound of this invention or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof.

In one embodiment, this invention provides a method of treating diabeticretinopathy in a human subject, comprising the step of administering tosaid subject a compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treating fattyliver conditions in a human subject, comprising the step ofadministering to said subject a selective androgen receptor modulatorcompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, or any combinationthereof.

In one embodiment, this invention provides a method of treatingovascular disease in a human subject, comprising the step ofadministering to said subject a compound of this invention or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, or any combination thereof.

In one embodiment this invention provides a method for a) treating,preventing, suppressing inhibiting atherosclerosis b) treating,preventing, suppressing inhibiting liver damage due to fat depositscomprising the step of administering to the subject a compound asdescribed herein and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal, or any combination thereof, or acomposition comprising the same, in an amount effective to treat,prevent or inhibit atherosclerosis and liver damage due to fat deposit.

In one embodiment, the compound as described herein is useful in a)treating, preventing, suppressing, inhibiting, or reducingatherosclerosis; b) treating, preventing, suppressing inhibiting liverdamage due to fat deposits.

In one embodiment atherosclerosis refers to a slow, complex disease thatmay begin with damage to the innermost layer of the artery. In anotherembodiment the causes of damage to the arterial wall may include a)elevated levels of cholesterol and in the blood; b) high blood pressure;c) tobacco smoke d) diabetes. In another embodiment, the condition istreatable in a smoker, despite the fact that tobacco smoke may greatlyworsen atherosclerosis and speed its growth in the coronary arteries,the aorta and arteries in the legs. Similarly, in another embodiment,the methods of this invention may be useful in treating subjects with afamily history of premature cardiovascular disease who have an increasedrisk of atherosclerosis.

In one embodiment, liver damage due to fat deposits refer to thebuild-up of fat in the liver cells forming a Fatty Liver which may beassociated with or may lead to inflammation of the liver. This can causescarring and hardening of the liver. When scarring becomes extensive, itis called cirrhosis.

In another embodiment the fat accumulates in the liver as obesity. Inanother embodiment fatty liver is also associated with diabetesmellitus, high blood triglycerides, and the heavy use of alcohol. Inanother embodiment fatty Liver may occur with certain illnesses such astuberculosis and malnutrition, intestinal bypass surgery for obesity,excess vitamin A in the body, or the use of certain drugs such asvalproic acid (trade names: Depakene/Depakote) and corticosteroids(cortisone, prednisone). Sometimes fatty liver occurs as a complicationof pregnancy.

In one embodiment, subjects with kidney disease, in particular malesubjects with end-stage renal disease (ESRD) suffer from hypogonadism,with some having concomitant moderate to severe protein-energymalnutrition (PEM), which leads to higher required doses of EPO, lowerQOL scores, and higher mortality. Many have other symptoms associatedwith hypogonadism, including fatigue, lack of apetite, muscle weakness,etc. In some embodiments, the treatment methods of this invention areuseful in treating symptoms associated with hypogonadism, brought aboutin the subject by the kidney disease or disorder.

In one embodiment, diabetic nephropathy is a complication of diabetesthat evolves early, typically before clinical diagnosis of diabetes ismade. The earliest clinical evidence of nephropathy is the appearance oflow but abnormal levels (>30 mg/day or 20 μg/min) of albumin in theurine (microalbuminuria), followed by albuminuria (>300 mg/24 h or 200μg/min) that develops over a period of 10-15 years. In patients withtype 1 diabetes, diabetic hypertension typically becomes manifest earlyon, by the time that patients develop microalbuminuria. Once overtnephropathy occurs, the glomerular filtration rate (GFR) falls over acourse of times, which may be several years, resulting in End StageRenal Disease (ESRD) in diabetic individuals.

Hypertension is another comorbid factor for renal disease. In someembodiments, treatment of renal disease according to the presentinvention may comprise concomitant treatment with a compound of thisinvention and an agent which treats hypertension.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, comprising the methods of thepresent invention include those conditions which are associated withaging. In one embodiment, the compound as described herein is useful ina) Age-related functional decline (ARFD); b) reversal or prevention ofARFD; c) reversal or prevention of ARFD in elderly d) reversal orprevention of ARFD-induced sarcopenia or osteopenia; e) Andropause,andropausal vasomotor symptoms, f) andropausal gynecomastia, musclestrength/function; g) bone strength/function; h) Anger; i) Asthenia; j)Chronic fatigue syndrome; k) Cognitive impairment; and/or l) improvingcognitive function.

In one embodiment, the compound as described herein is useful intreating inflammation and related disorders such as: a) prevention,treatment, or reversal of arthritis; b) prevention, treatment, orreveral of an arthritic condition such as Behcet's disease (autoimmunevasculitis), bursitis, calcium pyrophosphate dihydrate crystal (CPPD),deposition disease (or pseudogout), carpal tunnel syndrome, connectivetissue disorders, Crohn's diseases, Ehlers-Danlos syndrome (EDS),fibromyalgia, gout, infectious arthritis, inflammatory bowel disease(IBD), juvenile arthritis, systemic lupus erythematosus (SLE), Lyme'sdisease, Marfan syndrome, myositis, osteoarthritis, polyarteritisnodosa, polymyalgia rheumatica, psoriasis, psoriatic arthritis,Raynaud's phenomenon, reflex sympathetic dystrophy syndrome, Reiter'ssyndrome, rheumatoid arthritis, scleroderma, Sjögrens' syndrome,tendonitis or ulcerative colitis; c) preventing, treatment, or reversingan autoimmune disease.

In one embodiment, the compound as described herein is useful inprevention of iatrogenic effects comprising acute fatigue syndrome(post-surgical) or androgen-deprivation

therapy (ADT) induced side effects such as reduced muscle mass, reducedmuscle strength, frailty, hypogonadism, osteoporosis, osteopenia,decreased BMD and/or decreased bone mass.

In one embodiment, the compounds and/or compositions and/or methods ofuse thereof are for the treatment of human subjects, wherein, in oneembodiment, the subject is male, or in another embodiment, the subjectis female.

In one embodiment, the methods of the present invention compriseadministering a compound of this invention as the sole activeingredient. However, also encompassed within the scope of the presentinvention are methods for diabetes and related disorders, hormonetherapy, dry eye, obesity, treating prostate cancer, delaying theprogression of prostate cancer, and for preventing and/or treating therecurrence of prostate cancer, male contraception; treatment ofosteoporosis, treatment of conditions associated with ADIF and fortreatment and/or prevention of chronic muscular wasting which compriseadministering the compounds in combination with one or more therapeuticagents. These agents include, but are not limited to: LHRH analogs,reversible antiandrogens, antiestrogens, anticancer drugs, 5-alphareductase inhibitors, aromatase inhibitors, progestins, agents actingthrough other nuclear hormone receptors, selective estrogen receptormodulators (SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine,bisphosphonate, and one or more additional SARMs.

Thus, in one embodiment, the methods of the present invention compriseadministering the compound of this invention in combination withdiabetes drug such as Troglitazone, Rosiglitazone, and Pioglitazone. Inanother embodiment, the methods of the present invention compriseadministering the compound in combination with an LHRH analog. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with a reversibleantiandrogen. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anantiestrogen. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with ananticancer drug. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with a5-alpha reductase inhibitor. In another embodiment, the methods of thepresent invention comprise administering the compound, in combinationwith an aromatase inhibitor. In another embodiment, the methods of thepresent invention comprise administering the compound, in combinationwith a progestin. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anagent acting through other nuclear hormone receptors. In anotherembodiment, the methods of the present invention comprise administeringthe compound, in combination with a selective estrogen receptormodulators (SERM). In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with aprogesterone. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anestrogen. In another embodiment, the methods of the present inventioncomprise administering the compound, in combination with a PDE5inhibitor. In another embodiment, the methods of the present inventioncomprise administering the compound, in combination with apomorphine. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with a bisphosphonate. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with one or more additionalSARMs. In some embodiments, the methods of the present inventioncomprise combined preparations comprising the compound and an agent asdescribed hereinabove. In some embodiments, the combined preparationscan be varied, e.g., in order to cope with the needs of a patientsubpopulation to be treated or the needs of the single patient whichdifferent needs can be due to the particular disease, severity of thedisease, age, sex, or body weight as can be readily determined by aperson skilled in the art. In some embodiments, the methods of thepresent invention comprise personalized medicine methods which treat theneeds of a single patient. In one embodiment, different needs can be dueto the particular disease, severity of the disease, the overall medicalstate of a patient, or the age of the patient. In some embodiments,personalized medicine is the application of genomic data to bettertarget the delivery of medical interventions. Methods of personalizedmedicine, in some embodiments, serve as a tool in the discovery andclinical testing of new products of the present invention. In oneembodiment, personalized medicine involves the application of clinicallyuseful diagnostic tools that may help determine a patient'spredisposition to a particular disease or condition. In someembodiments, personalized medicine is a comprehensive approach utilizingmolecular analysis of both patients and healthy individuals to guidedecisions throughout all stages of the discovery and development ofpharmaceuticals and diagnostics; and applying this knowledge in clinicalpractice for a more efficient delivery of accurate and qualityhealthcare through improved prevention, diagnosis, treatment, andmonitoring methods.

Oxidative damage can comprise damage to cells and tissue, caused byoxidation of various cellular products, which through the production ofperoxides and free radicals damage components of the cell and tissue,for example, damaging cell integrity, cell membranes, DNA, etc.

In another embodiment, the invention provides a method of treating,preventing, inhibiting reducing the incidence of oxidativedamage-related diseases, disorders or conditions in a subject,comprising administering a pharmaceutical composition comprising a SERMof formula (I)-(XI) or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, ester, hydrate or any combinationthereof, thereby treating, preventing, inhibiting reducing the incidenceof oxidative damage-related diseases in a subject.

In some embodiments, the oxidative damage-related diseases, disorders orconditions may comprise cancers; skin disorders; neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Huntington'sdisease, multiple sclerosis, and amyotrophic lateral sclerosis; vasculardiseases such as stroke and various age-related dementias, andatherosclerosis; or age-related macular degeneration.

Inflammation is a common and potentially debilitating condition thatoccurs when the white blood cells and endogenous chemicals that canprotect us from infection and foreign substances such as bacteria andviruses act on tissue surrounding a wound or infection. In somediseases, however, the body's defense system (immune system) triggers aninflammatory response when there are no foreign substances to fight off.In these diseases, called autoimmune diseases, the body's normallyprotective immune system causes damage to its own tissues. The bodyresponds as if normal tissues are infected or somehow abnormal. Some,but not all types of arthritis are the result of misdirectedinflammation. Arthritis is a general term that describes inflammation injoints and affects more than 2-4% of the world's population. There aremany medications available to decrease swelling and inflammation andhopefully prevent or minimize the progression of the inflammatorydisease. The medications include non-steroidal anti-inflammatory drugs(NSAIDs—such as aspirin, ibuprofen or naproxen), corticosteroids (suchas prednisone), anti-malarial medications (such as hydroxychloroquine),and other medications including gold, methotrexate, sulfasalazine,penicillamine, cyclophosphamide and cyclosporine.

The role of estrogen receptor and its ligands as therapy forinflammation has been under consideration. The effects are regarded tobe mediated by the isoform ER-β. Treatment of rats with estradiol orSERMs such as raloxifene and tamoxifen has been shown to reduce theincidence of lipo-polysacharride induced inflammatory responses. One ofthe pathways through which inflammatory responses are mediated isthrough the activation of NFκB pathway. Nuclear receptor ligands inhibitthe NFκB activity through protein interaction. Recently it was shownthat SERMs inhibit the inflammatory responses by inhibiting the NFκBfunction without having estrogenic effects on other reproductivetissues.

In one embodiment, the NRBA or SERM compounds as described herein areuseful in treating inflammation and related disorders such as: a)prevention, treatment, or reversal of arthritis; b) prevention,treatment, or reveral of an arthritic condition such as Behcet's disease(autoimmune vasculitis), bursitis, calcium pyrophosphate dihydratecrystal (CPPD), deposition disease (or pseudogout), carpal tunnelsyndrome, connective tissue disorders, Crohn's diseases, Ehlers-Danlossyndrome (EDS), fibromyalgia, gout, infectious arthritis, inflammatorybowel disease (IBD), juvenile arthritis, systemic lupus erythematosus(SLE), Lyme's disease, Marfan syndrome, myositis, osteoarthritis,polyarteritis nodosa, polymyalgia rheumatica, psoriasis, psoriaticarthritis, Raynaud's phenomenon, reflex sympathetic dystrophy syndrome,Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjögrens'syndrome, tendonitis or ulcerative colitis; c) preventing, treatment, orreversing an autoimmune disease; d) chronic kidney disease (CKD).

In another embodiment, the invention provides a method of treating,preventing, inhibiting reducing the incidence of inflammatory diseases,disorders or conditions in a subject, comprising administering apharmaceutical composition comprising a SERM of formula (I)-(XI) or itsprodrug, analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,N-oxide, ester, hydrate or any combination thereof, thereby treating,preventing, inhibiting reducing the incidence of inflammatory conditionsin a subject. In some embodiments ER-β agonists are useful in treating,preventing, inhibiting reducing the incidence of inflammatory diseases,disorders or conditions in a subject. In another embodiment, ER-βagonist of this invention is compound 3a, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 3d, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 3e, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 3l, listed in Table 1. In another embodiment,ER-β agonist of this invention is compound 3g, listed in Table 1. Inanother embodiment, ER-β agonist of this invention is compound 3j,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 3i, listed in Table 1, or any combination thereof. Inanother embodiment, ER-β agonist of this invention is compound 4a,listed in Table 1. In another embodiment, ER-β agonist of this inventionis compound 4h, listed in Table 1. In another embodiment, ER-β agonistof this invention is compound 4u, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10o, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10d, listed in Table 1. In another embodiment, ER-β agonist ofthis invention is compound 10f, listed in Table 1. In anotherembodiment, ER-β agonist of this invention is compound 10l, listed inTable 1. In another embodiment, ER-β agonist of this invention iscompound 10w, listed in Table 1, or any combination thereof.

In some embodiments, ER-β agonists of this invention inhibitstroma-epithelial proliferation (FIG. 3, Example 4) which can affect thedevelopment of anatomic obstruction, which can reduce inflammation andthereby, treat inflammation. In one embodiment, ER-β agonists of thisinvention relax smooth muscle which can lower urinary tract symptoms,affect the development of BPH, which can reduce inflammation andthereby, treat inflammation.

In some embodiments, the inflammatory diseases disorders or conditionswhich may comprise acute inflammation, arthropathies (in general),rheumatoid arthritis, systemic lupus erythema, asthma, acuteinflammation, chronic inflammation, joint damage, joint swelling, jointerosion, sepsis, or any combination thereof.

In one embodiment, joint inflammation is one of the most common causesof pain, lameness, and loss of physical activity, not only in humans butin animals, particularly horses. This debilitating condition is markedby edema, redness, heat and pain. If left untreated, joint inflammationalso can lead to destruction of the joint synovium and the articularcartilage producing a permanent debilitating condition. The edema,redness, and pain that occur during inflammation are the result ofphysiological changes in the joint. For example, the permeability of thesynovial membrane increases during inflammation allowing synovial fluidto leak into the tissues of the joint. Alterations in blood flow andpressure in the vascular system of the joint also occur duringinflammation. In addition, the metabolic activity of the cells of thejoint increases during inflammation.

In another embodiment, the invention provides a method of treating,preventing, inhibiting reducing the incidence of joint inflammation in asubject, comprising administering a pharmaceutical compositioncomprising a SERM of formula (I)-(XI) or its prodrug, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, ester, hydrate or anycombination thereof, thereby treating, preventing, inhibiting reducingthe incidence of joint inflammation in a subject.

In one embodiment, the NRBAs or SERMs of this invention bind theircognate receptor at the cell surface, translocate to the cell's nucleus,and exerts their effects. In one embodiment, such effects may comprise,inter alia, regulation of particular gene expression, and may in turnplay a role in the inhibition of apoptosis, activation of protein kinasepathways, and others.

In another embodiment, the NRBAs or SERMs of this invention bind cognatereceptors and translocate within the mitochondria, whereupon theyassociate with mitochondrial DNA, and in turn play a role in theincreased respiratory chain activity, inhibition of TGFβ-inducedapoptosis and/or activation of manganese superoxide dismutase, andothers.

Superoxide dismutases (SODs) are key enzymes in the cellular defenseagainst free radical oxidation. By catalyzing the degradation of thesuperoxide free radical to water and hydrogen peroxide, SODs, play animportant role in reducing the damage associated with, for exampleischemic injury, chronic lung disease, Alzheimer's disease, Downsyndrome, inflammatory disorders, cardiovascular disease, immune-systemdecline, brain disfunction, cataracts, and other aspects of aging anddegenerative disease.

In one embodiment, this invention provides a method of treating,ameliorating and/or preventing reactive species-mediated damage in asubject, comprising the step of administering a NRBA or SERM of formula(I)-(XI) or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, ester, hydrate or any combination thereof tothe subject. In one embodiment, the reactive species comprises reactiveoxygen intermediates and the NRBA promotes or enhances the activity ofcellular superoxide dismutase. In one embodiment, the reactive speciescomprises reactive nitrogen intermediates and the NRBA promotes orenhances the activity of cellular nitric oxide synthase.

In some embodiments, such damage is associated with a variety ofdiseases, such as, but not limited to cardiovascular disease, such ascoronary heart disease and atherosclerosis, neurodegenerative disease,such as Alzheimer's disease and/or multiple sclerosis, infection, forexample, HCV infection and complications thereof, autoimmune disease,such as lupus, cancer, and others, as appreciated by one skilled in theart.

In some embodiments, such activity results in suppression of pathogenicapoptosis, for example, as occurs in various disease states, such asneurodegenerative diseases or disorders, glaucoma, autoimmune disease,and others as will be appreciated by one skilled in the art.

In some embodiments, the compounds of this invention, characterized bythe structures of formulae I-XI, and including any embodiment thereof,localize within the cytosol of a cell, or within cytosolic organelles,such as mitochondrion, wherein such compounds may affect cellularsignaling pathways, and thereby effect the methods as described herein.For example, and in one embodiment, the compounds may interact withcellular proteins and thereby synergize a desired effect, in someembodiments, in signaling pathways within the cell, producing thedesired effect. In other embodiments, the compounds of formulae I-XIantagonize a particular response or pathway in the cell, which otherwiseproduces an undesired effect, for example, exacerbating disease, andthus the compounds as described herein are effective in such methods bytheir ability to disrupt or interfere or antagonize pathogenicmechanisms in a cell or in a subject.

In some embodiments, the agents of this invention, may alterintracellular signaling pathways or responsiveness to such pathways orcascades.

In some embodiments, downstream effects of the compounds of thisinvention, characterized by the structures of formulae I-XI, andincluding any embodiment thereof, may be controlled by intracellularkinase signaling pathways activated by growth factors. In someembodiments, the compounds may affect signaling downstream of binding ofa hormone to its receptor, for example, with the case of glycogensynthase kinase 3 (GSK3), an effector kinase of the phosphatidylinositol3-kinase (PI3K) pathway, may be activated by administration of acompound of this invention and in turn affect ERalpha activity inspecific cells, for example in neuroblastoma cells, and thereby effectsome of the methods of this invention. In some embodiments, thecompounds of this invention may result in greater expression of GSK3,which in turn stimulates or increases ER-dependent gene expression.

It is to be understood that any use of any of the compounds as hereindescribed may be used in the treatment of any disease, disorder orcondition as described herein, and represents an embodiment of thisinvention.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1 Novel SERMs and their Estrogen Receptor BindingAffinities, Agonist and Antagonist Activity Materials and Methods

ER binding affinity was determined via one of the following methods:

Method 1:

Human recombinant ER was expressed in insect Sf9 cells and performed aradioactive competitive binding assay with tritiated estradiol. If theNRBA compounds tested showed a ≧50% inhibition of [³H] estradiol bindingat 1 μM (1000 nM) concentration, they were tested using fourconcentrations of the compound to give an estimated IC₅₀ and K_(i)value.

Method 2:

Estrogen receptor (ER) binding affinity of NRBA compounds was alsodetermined using an in vitro competitive radioligand-binding assay with[³H]-estradiol ([³H]-E₂, PerkinElmer), a high affinity ligand for bothERα and ERβ. The equilibrium dissociation constant (K_(d)) of [³H]-E₂was determined by incubating increasing concentrations of [³H]-E₂ (0.01to 10 nM) with bacterial expressed ERα or β ligand binding domain (LBD)at 4° C. for 18 h. Non-specific binding was determined by adding 1000 nME₂ to the incubation mixture. It was determined that the minimumconcentration of [³H]-E₂ required to saturate ERα and ERβ binding sitesin the incubation mixture was 1 nM, respectively. The binding affinityof the NRBA compounds was determined under identical conditions byincubating increasing concentrations (3×10⁻² to 1,000 nM) of ligand withisolated ER LBD and 1 nM [³H]-E₂. Following incubation, bound and free[³H]-E₂ was separated by using vacuum filtration with the Harvester(PerkinElmer). Briefly, the incubation mixture was filtered through ahigh affinity protein binding filter, and washed several times to removeany unbound radioactivity. The filter plate was air dried and sealed onthe bottom. Scintillation cocktail was added to each well and the top ofthe plate was sealed. Radioactivity was counted in a TopCount NXTMicroplate Scintillation Counter.

Specific binding of [³H]-E₂ (B) at each concentration of SERM wasobtained by subtracting the nonspecific binding of [³H]-E₂, andexpressed as a percentage of the specific binding of [³H]-E₂ in theabsence of SERM (B₀). The concentration of SERM that reduced thespecific binding of [³H]-E₂ by 50% (IC₅₀) was determined bycomputer-fitting the data by nonlinear regression analysis usingSigmaPlot (SPSS Inc., Chicago, Ill.) to the following equation:B=B ₀*[1−C/(IC₅₀ +C)]

where C is the concentration of SERM.

The equilibrium dissociation constant (K_(i)) of SERM was calculated by:K _(i) =K _(d)*IC₅₀/(K _(d) +L)

where K_(d) is the equilibrium dissociation constant of [³H]-E₂(ERα=0.65 nM, ERβ=1.83 nM),

and L is the concentration of [³H]-E₂ (1 nM).

Table 1 presents a series of NRBA compounds. Representative NRBAs aredescribed hereinbelow, whose activity under specific experimentalconditions is provided. It is to be understood that while the indicatedcompounds may exhibit a particular activity (for example, compound 3v isan agonist) under the experimental conditions employed, as a function,in some embodiments of the particular cells utilized, etc., suchcompounds may possess alternate or varied activity in differentexperimental settings.

Representative examples of the NRBAs of this invention and theiractivity under the indicated conditions are as follows:

-   -   ER alpha agonists: 3v (ER-α: K_(i)=20 nM; EC₅₀=22.4 nM), 3b        (ER-α: K_(i)=14 nM; EC₅₀=10 nM), 3k (ER-α: K_(i)=129 nM; EC₅₀=12        nM), 10x (ER-α: K_(i)=13 nM; EC₅₀=16 nM).    -   ER alpha antagonists: 10m (ER-α: K_(i)=221 nM; IC₅₀=<10 nM), 4a        (ER-α: K_(i)=111 nM; IC₅₀=35 nM), 11f (ER-α: K_(i)=60 nM;        IC₅₀=69 nM), and 11g (ER-α: K_(i)=79 nM; IC₅₀=16 nM)    -   ER beta agonists: 10d (ER-β: K_(i)=61 nM; EC₅₀=85 nM), 10f        (ER-β: K_(i)=57 nM; EC₅₀=42 nM), 101 (ER-β: K_(i)=82 nM; EC₅₀=27        nM), 11p (ER-β: K_(i)=108 nM; EC₅₀=<10 nM)    -   ER beta antagonist: 10j (ER-β: K_(i)=36 nM; IC₅₀=20 nM), 10n        (ER-β: K_(i)=92 nM; IC₅₀=47 nM), 10t (ER-β: K_(i)=<10 nM;        IC₅₀=17 nM)

TABLE 1 Compound # and IUPAC NAME PHYSICAL CHARACTERIZATION Estradiol(E2) Propyl pyrazole triol (PPT) Dipropionitrile (DPN) ICI-182780 5d tansolid. 95% yield. M.p. 239-241° C. ¹H NMR (DMSO-d₆, 4-Hydroxy-N-(4- 300MHz) δ 9.80 (bs, 1H), 9.46 (bs, 1H), 7.23-7.21 (m, 2H),hydroxyphenyl)-N-(4- 7.08-7.05 (m, 2H), 6.96-6.93 (m, 2H), 6.87-6.84 (m,2H), methoxyphenyl)-benzamide 6.68-6.65 (m, 2H), 6.60-6.57 (m, 2H), 3.72(s, 3H). MS m/z 334 (M − H)⁻. 5e tan solid. 90% yield. M.p. 205-206° C.¹H NMR (DMSO-d₆, N-(4-Hydroxyphenyl)-4- 300 MHz) δ 9.48 (bs, 1H),7.35-7.32 (m, 2H), 6.99-6.97 (m, methoxy-N-(4-methoxyphenyl)- 2H),6.87-6.85 (m, 2H), 6.81-6.77 (m, 2H), 6.68-6.66 (m, benzamide 2H), 3.72(s, 6H). MS m/z 348 (M − H)⁻. 4n white solid. 88% yield. M.p. 163-165°C. ¹H NMR (DMSO- 4-Methoxy-N-(4- d₆, 300 MHz) δ 7.36 (d, 2H, J = 8.69Hz), 7.16-7.07 (m, 4H), methoxyphenyl)-N-[4-(2- 6.94 (d, 2H, J = 8.82Hz), 6.87 (d, 2H, J = 8.82 Hz), 6.80 (d, piperidin-1-ylethoxy)phenyl]-2H, J = 8.75 Hz), 4.38-4.35 (m, 2H), 3.69 (s, 6H), benzamide 3.48-3.44(m, 4H), 2.51-2.50 (m, 2H), 1.78-1.66 (m, 4H), 1.41-1.37 (m, 2H). MS m/z461 (M + H)⁺. 3u tan solid. 21% yield. M.p. 232-234° C. ¹H NMR (DMSO-d₆,N-Biphenyl-4-yl-N-(4- 300 MHz) δ 9.55 (s, 1H). 7.65-7.62 (m, 4H), 7.45(t, 1H, J = 7.69 Hz), hydroxyphenyl)-4- 7.40-7.34 (m, 4H), 7.23 (d, 2H,J = 8.55 Hz), methoxybenzamide 7.03-7.02 (m, 2H), 6.82-6.80 (m, 2H),6.71-6.69 (m, 2H), 3.73 (s, 3H),. MS m/z 418 (M + Na)⁺. 3v white solid.49% yield. M.p. 253-255° C. ¹H NMR (DMSO-N-Biphenyl-4-yl-4-hydroxy-N-(4- d₆, 300 MHz) δ 7.65-7.61 (m, 4H), 7.45(t, 2H, J = 7.69 Hz), hydroxyphenyl)-benzamide 7.36-7.33 (m, 1H),7.28-7.26 (m, 2H), 7.21-7.19 (m, 2H), 7.01-6.98 (m, 2H), 6.71-6.68 (m,2H), 6.62-6.60 (m, 2H). MS m/z 404 (M + Na)⁺. 3w tan solid. 46% yield.M.p. 233-235° C. ¹H NMR (DMSO-d₆, 4-Hydroxy-N-(4- 300 MHz) δ 9.81 (bs,1H), 9.47 (bs, 1H), 7.24-7.20 (m, 2H), hydroxyphenyl)-N-[4-(2- 7.05-7.03(m, 2H), 6.96-6.93 (m, 2H), 6.87-6.84 (m, 2H),piperidin-1-ylethoxy)phenyl]- 6.68-6.65 (m, 2H), 6.60-6.57 (m, 2H),4.02-3.99 (m, 2H), benzamide 2.63-2.60 (m, 2H), 2.09-2.08 (m, 4H),1.48-1.36 (m, 6H). MS m/z 433 (M + H)⁺. 2w pale-yellow solid. 96% yield.M.p. 125-128° C. ¹H NMR 4-Cyano-N-(4-methoxyphenyl)- (DMSO-d₆, 300 MHz)δ 7.77-7.74 (m, 2H), 7.61-7.58 (m, N-phenylbenzamide 2H), 7.34-7.21 (m,7H), 6.88 (d, 2H, J = 7.92 Hz), 3.71 (s, 3H). MS m/z 351 (M + Na)⁺. 4opale-yellow solid. 40% yield. M.p. 132-135° C. ¹H NMRN-Biphenyl-4-yl-N-(4- (DMSO-d₆, 300 MHz) δ 7.65-7.61 (m, 4H), 7.47-7.45(m, hydroxyphenyl)-4-(2-piperidin- 2H), 7.36-7.33 (m, 1H), 7.28-7.26 (m,2H), 7.21-7.19 (m, 1-ylethoxy)-benzamide 2H), 7.01-6.98 (m, 2H),6.70-6.67 (m, 2H), 6.62-6.61 (m, 2H), 4.05 (bs, 2H), 2.66 (bs, 2H),2.50-2.45 (m, 4H), 1.49-1.38 (m, 6H). MS m/z 493 (M + H)⁺. 3x tan solid.78% yield. M.p. 221-222° C. ¹H NMR ((DMSO-d₆, 3-Hydroxy-N-(4- 300 MHz) δ9.51 (bs, 2H), 7.33-7.29 (m, 2H), 7.19-7.15 (m, hydroxyphenyl)-N-phenyl-3H), 7.04-6.98 (m, 3H), 6.82-6.66 (m, 5H). MS m/z 304 (M − H)⁻.benzamide 10a yellow solid, 74% yield, M.p. 243-244° C. ¹H NMR (DMSO-4-cyano-N-(4-hydroxyphenyl)- d₆, 300 MHz) δ 7.76-7.74 (m, 1H), 7.58-7.56(m, 2H), N-phenylbenzamide 7.33-7.21 (m, 5H), 7.09-7.08 (m, 2H), 6.67(s, 2H). MS m/z 313 (M − H)⁻. 4p yellow solid. 84% yield. M.p. 139-141°C. ¹H NMR (DMSO- 4-Methoxy-N-phenyl-N-[4-(2- d₆, 300 MHz) δ 7.35-7.33(m, 4H), 7.26-7.22 (m, 5H), piperidin-1-ylethoxy)phenyl]- 7.15-7.14 (m,2H), 7.12-7.11 (m, 2H), 6.91-6.87 (m, 2H), benzamide 6.83-6.80 (m, 2H),4.02 (t, 2H, J = 5.79 Hz), 3.72 (s, 3H), 2.63 (t, 2H, J = 5.79 Hz), 2.41(bs, 4H), 1.48-1.46 (m, 4H), 1.38-1.36 (m, 2H). MS m/z 507 (M + H)⁺. 2ybrown oil. 85% yield. ¹H NMR (DMSO-d₆, 300 MHz)4-Cyano-N-(3-methoxyphenyl)- δ 7.77-7.75 (m, 2H). 7.63-7.61 (m, 2H),7.35-7.30 (m, 4H), N-phenylbenzamide 7.25-7.22 (m, 2H), 6.91 (s, 1H),6.83-6.80 (m, 2H), 3.67 (s, 3H). MS m/z 351 (M + Na)⁺. 2z tan solid. 85%yield. M.p.145-147° C. ¹H NMR (DMSO-d₆, 4-Cyano-N,N- 300 MHz) δ7.76-7.74(m, 2H), 7.61-7.59 (m, 2H), diphenylbenzamide 7.34-7.22 (m, 10H). MS m/z321 (M + Na)⁺. 4q tan solid. 64% yield. M.p. 93-95° C. ¹H NMR (DMSO-d₆)N-(4-Hydroxyphenyl)-N-phenyl- δ 9.56 (d, 1H, J = 6.00 Hz), 7.35-7.30 (m,2H), 7.23-7.14 (m, 3-(2-piperidin-1-ylethoxy)- 4H), 7.05-6.76 (m, 5H),6.69-6.67 (m, 2H), 4.20 (bs, 2H), benzamide 2.81-2.73 (m, 6H), 1.48 (bs,4H), 1.46 (bs, 2H). MS m/z 417 (M + H)⁺. 3y pale-yellow solid. 46%yield. M.p.109-112° C. ¹H NMR N-Biphenyl-4-yl-4-hydroxy-N-[4- ((DMSO-d₆,300 MHz) δ 9.89 (s, 1H), 7.65-7.61 (m, 4H),(2-piperidin-1-ylethoxy)phenyl]- 7.46-7.43 (m, 2H), 7.37-7.33 (m, 1H),7.31-7.28 (m, 2H), benzamide 7.22-7.19 (m, 2H), 7.12-7.09 (m, 2H),6.91-6.89 (m, 2H), 6.63-6.60 (m, 2H), 4.04 (bs, 2H), 2.67-2.64 (m, 2H),2.46 (bs, 4H), 1.50-1.49 (m, 4H), 1.37 (bs, 2H). MS m/z 493 (M + H)⁺.10b yellow solid, 70% yield, M.p. 209-211° C. ¹H NMR (DMSO-N-(biphenyl-4-yl)-4-cyano-N-(4- d₆, 300 MHz) δ 7.78-7.77 (m, 2H),7.65-7.63 (m, 6H), methoxyphenyl)-benzamide 7.47-7.44 (m, 2H), 7.37-7.34(m, 3H), 7.27-7.25 (m, 2H). 6.89 (bs, 2H), 3.72 (s, 3H). MS m/z 405 (M +H)⁺. 10c tan solid, 72% yield, M.p. > 250° C. ¹H NMR (DMSO-d₆, 300 MHz)N,N-bis(4- δ 9.49 (s, 2H), 7.66-7.64 (m, 2H), 7.58-7.56 (m, 6H),hydroxyphenyl)biphenyl-4- 7.46-7.42 (m, 4H), 7.38-7.35 (m, 1H),7.05-7.03 (m, 4H). carboxamide 6.69 (bs, 4H). MS m/z 382 (M + H)⁺. 10dtan solid, 68% yield, M.p. > 250° C. ¹H NMR (DMSO-d₆, 300 MHz)N,N-bis(4-hydroxyphenyl)-3,4- δ 9.46 (s, 3H), 7.20 (s, 1H), 7.03-6.95(m, 6H), dimethylbenzamide 6.68-6.65 (m, 4H), 2.14 (s, 3H), 2.12 (s,4H). MS m/z 334 (M + H)⁺. 10e yellow solid, 58% yield, M.p. 223-224° C.¹H NMR (DMSO- N-(biphenyl-4-yl)-4-cyano-N-(4- d₆, 300 MHz) δ 9.63 (s,3H), 7.78-7.76 (m, 2H), 7.66-7.60 (m, hydroxyphenyl)-benzamide 6H),7.48-7.43 (m, 2H), 7.38-7.35 (m, 3H), 7.12 (d, 2H, J = 8.27 Hz), 6.69(d, 2H, J = 8.27 Hz). MS m/z 334 (M + H)⁺. 10f white solid, 66% yield,M.p. 223-225° C. ¹H NMR (DMSO- 3-fluoro-4-hydroxy-N-(4- d₆, 300 MHz) δ10.11 (bs, 1H), 9.57 (bs, 1H), 7.34-7.29 (m, hydroxyphenyl)-N- 2H),7.20-7.10 (m, 4H), 7.06-6.97 (m, 3H), 6.81-6.75 (m, phenylbenzamide 1H),6.70-6.67 (m, 2H). MS m/z 324 (M + H)⁺. 10g tan solid, 71% yield, M.p. >250° C. ¹H NMR (DMSO-d₆, 300 MHz) 4-fluoro-3-hydroxy-N,N-bis(4- δ 9.95(bs, 1H), 9.47 (bs, 2H), 7.02-6.95 (m, 6H), hydroxyphenyl)-benzamide6.75-6.72 (m, 1H), 6.68-6.66 (m, 4H). MS m/z 340 (M + H)⁺. 10i tansolid, 91% yield, M.p. > 250° C. ¹H NMR (DMSO-d₆, 300 MHz)4-hydroxy-N,N-bis(4- δ 9.41 (bs, 2H), 6.96-6.92 (m, 6H), 6.66 (d, 4H, J= 8.79 Hz), hydroxyphenyl)-3,5- 2.02 (s, 6H). MS m/z 350 (M + H)⁺.dimethylbenzamide 10j peach-white solid, 68% yield, M.p. > 250° C. ¹HNMR N,N-bis(4-hydroxyphenyl)-2,3- (DMSO-d₆, 300 MHz) δ 9.47 (bs, 2H),7.18 (d, 2H, J = 8.30 Hz), dimethylbenzamide 7.06 (d, 1H, J = 7.08 Hz),7.00-6.92 (m, 4H), 6.78 (d, 2H, J = 8.30 Hz), 6.51 (d, 2H, J = 8.06 Hz),2.22 (s, 3H), 2.15 (s, 3H). MS m/z 334 (M + H)⁺. 10k tan solid, 71%yield, M.p. > 250° C. ¹H NMR (DMSO-d₆, 300 MHz)3-fluoro-4-hydroxy-N,N-bis(4- δ 10.25 (bs, 1H), 9.48 (bs, 2H), 7.12-6.95(m, 6H), hydroxyphenyl)-benzamide 6.80-6.65 (m, 5H). MS m/z 338 (M −H)⁻. 10l tan solid, 77% yield, M.p. 224-225° C. ¹H NMR (DMSO-d₆,N,N-bis(4-hydroxyphenyl)-4- 300 MHz) δ 9.46 (s, 2H), 7.27-7.26 (m 2H),7.06-7.04 (m, propylbenzamide 2H), 6.99-6.97 (m, 4H), 6.66-6.65 (m, 4H),2.50 (s, 2H), 1.53-1.52 (m, 2H), 0.82 (t, 3H, J = 7.33 Hz). MS m/z 346(M − H)⁻. 10m light-pink solid, 66% yield, M.p. > 250° C. ¹H NMR (DMSO-3,4-dihydroxy-N,N-bis(4- d₆, 300 MHz) δ 9.39 (bs, 4H), 6.91 (d, 2H, J =8.79 Hz), hydroxyphenyl)-benzamide 6.84 (d, 1H, J = 1.95 Hz), 6.66 (d,4H, J = 8.55 Hz), 6.62-6.60 (m, 1H), 6.51 (d, 1H, J = 8.30 Hz). MS m/z336 (M − H)⁻. 10n tan solid, 78% yield, M.p. > 250° C. ¹H NMR (DMSO-d₆,300 MHz) 4-hydroxy-N,N-bis(4- δ 9.69 (bs, 1H), 9.44 (bs, 2H), 7.15 (d,1H, J = 1.71 Hz), hydroxyphenyl)-3- 6.97 (dd, 2H, J = 1.95, 8.30 Hz),6.93 (d, 4H, J = 8.55 Hz), methylbenzamide 6.66 (d, 4H, J = 8.80 Hz),6.55 (d, 1H, J = 8.55 Hz), 2.50 (s, 3H). MS m/z 334 (M − H)⁻. 10o yellowsolid, 39% yield, M.p.168-171° C. ¹H NMR (DMSO-N-(4-hydroxyphenyl)-N-(4-(2- d₆, 300 MHz) δ 9.49 (s, 1H), 7.28 (d, 2H, J= 7.28 Hz), (piperidin-1-yl)ethoxy)phenyl)-4- 7.09 (d, 2H, J = 8.06 Hz),7.06 (d, 2H, J = 8.30 Hz), 6.99 (d, 2H, J = 8.06 Hz), propylbenzamide6.86 (d, 2H, J = 7.82 Hz), 6.66 (d, 2H, J = 7.57 Hz), 4.00 (bs, 2H),2.62 (bs, 2H), 2.51-2.50 (m, 2H), 2.40 (bs, 4H), 1.54-1.46 (m, 6H),1.37-1.36 (m, 2H), 0.82 (t, 3H, J = 7.33 Hz). MS m/z 459 (M + H)⁺. 10ptan foam, 32% yield, M.p. 93-96° C. ¹H NMR (DMSO-d₆,N-(4-hydroxyphenyl)-2,3- 300 MHz) δ 9.46 (s, 1H), 7.28 (d, 1H, J = 7.82Hz), 7.18 (d, dimethyl-N-(4-(2-(piperidin-1- 1H, J = 7.08 Hz), 7.08 (d,2H, J = 7.08 Hz), 6.99-6.91 (m, yl)ethoxy)phenyl)-benzamide 4H), 6.77(d, 1H, J = 7.33 Hz), 6.70 (d, 1H, J = 7.33 Hz), 6.51 (d, 1H, J = 7.57Hz), 4.07 (bs, 1H), 3.91 (bs, 1H), 2.68-2.64 (m, 2H), 2.50-2.35 (m, 4H),2.22 (s, 3H), 2.14 (s, 3H), 1.50-1.37 (m, 6H). MS m/z 445 (M + H)⁺. 10qyellow solid, 80% yield, M.p. 227-228° C. ¹H NMR (DMSO-N,N-bis(4-hydroxyphenyl)-2,4- d₆, 300 MHz) δ 9.45 (bs, 2H), 7.10-7.08(m, 4H), dimethylbenzamide 6.99-6.83 (m, 3H), 6.81-6.54 (m, 4H), 2.28(s, 3H), 2.17 (s, 3H). MS m/z 334 (M + H)⁺. 10r white solid, 61% yield,M.p. > 250° C. ¹H NMR (DMSO-d₆, N,N-bis(4-hydroxyphenyl)-3,5- 300 MHz) δ9.45 (bs, 2H), 7.10-7.08 (m, 4H), 6.98-6.83 (m, dimethylbenzamide 3H),6.81-6.54 (m, 4H), 2.28 (s, 3H), 2.17 (s, 3H). MS m/z 334 (M + H)⁺. 10stan solid, 32% yield, M.p. 223-225° C. ¹H NMR (DMSO-d₆,N,N-bis(4-hydroxyphenyl)-4- 300 MHz) δ 9.47 (bs, 2H), 7.25 (d, 2H, J =8.04 Hz), methylbenzamide 7.05-6.97 (m, 6H), 6.66 (d, 4H, J = 8.33 Hz),2.23 (s, 3H). MS m/z 320 (M + H)⁺. 10t tan foam, 41% yield, M.p.147-150° C. ¹H NMR (DMSO-d₆, 4,4′-(2,3-dimethyl- 300 MHz) δ 8.92 (s,2H), 7.07 (d, 1H, J = 7.33 Hz), 1), benzylazanediyl)diphenol 7.00-6.94(m, 2H), 6.76-6.72 (m, 4H), 6.63-6.59 (m, 4H), 4.72 (s. 2H), 2.23 (s,3H), 2.16 (s, 3H). MS m/z 320 (M + H)⁺. 10u yellow foam, 50% yield, M.p.117-122° C. ¹H NMR (DMSO- 4-formyl-N,N-bis(4- d₆, 300 MHz) δ 9.98 (s,1H), 9.52 (s, 2H), 7.78 (d, 2H, J = 8.13 Hz), hydroxyphenyl)-benzamide7.61 (d, 2H, J = 8.13 Hz), 7.06 (bs, 4H), 6.67 (bs, 4H). MS m/z 332 (M −H)⁻. 10v 4-hydroxy-N-(4- hydroxyphenyl)benzamide (10v) 11l yellow solid,67% yield, M.p. 146-148° C. ¹H NMR (DMSO- 4-((hydroxyimino)methyl)-N,N-d₆, 300 MHz) δ 11.36 (s, 1H), 9.49 (s, 2H), 8.07 (s, 1H),bis(4-hydroxyphenyl)benzamide 7.45 (d, 2H, J = 8.28 Hz), 7.37 (d, 1H, J= 8.28 Hz), 7.01 (d, 4H, J = 7.52 Hz), 6.67 (d, 4H, J = 6.45 Hz). MS m/z349 (M + H)⁺. 11m pale-yellow foam, 26% yield, M.p. 92-95° C. ¹H NMRN-(4-hydroxyphenyl)-2,4- (DMSO-d₆, 300 MHz) δ 9.48 (s, 1H), 7.13-6.81(m, 11H), dimethyl-N-(4-(2-(piperidin-1- 3.33 (bs, 2H), 2.65 (bs, 2H),2.51-2.45 (m, 4H), 2.29 (s, 3H), yl)ethoxy)phenyl)benzamide 2.17 (s,3H), 1.49 (bs, 4H), 1.38 (bs, 2H). MS m/z 446 (M + H)⁺. 11n pale-yellowfoam, 26% yield, M.p. 94-100° C. ¹H NMR N-(4-hydroxyphenyl)-3,5-(DMSO-d₆, 300 MHz) δ 9.50 (s, 1H), 7.11 (d, 2H, J = 8.67 Hz),dimethyl-N-(4-(2-(piperidin-1- 7.02-6.98 (m, 3H), 6.91-6.86 (m, 3H),6.67 (d, 2H, J = 8.46 Hz), yl)ethoxy)phenyl)benzamide 4.03 (t, 2H, J =5.10 Hz), 2.67 (bs, 2H), 2.51-2.46 (m, 4H), 2.15 (s, 6H), 1.50-1.49 (m,4H), 1.39-1.37 (m, 2H). MS m/z 445. 11o purple foam, 38% yield, M.p.65-70° C. ¹H NMR (DMSO-d₆, 4-((2,3-dimethylbenzyl)(4-(2- 300 MHz) δ 9.08(s, 1H), 7.08-6.86 (m, 5H), 6.78-6.65 (m, (piperidin-1- 6H), 4.75 (s,2H), 3.96 (t, 2H, J = 5.83 Hz), 3.34 (bs, 2H),yl)ethoxy)phenyl)amino)phenol 2.65 (bs, 2H), 2.51 (bs, 2H), 2.27 (s,3H), 2.16 (s, 3H), 1.51-1.48 (m, 4H), 1.38-1.37 (m, 2H). MS m/z 432. 11pwhite solid, 68% yield, M.p. 201-202° C. ¹H NMR (DMSO-N,N-bis(4-hydroxyphenyl)-4- d₆, 300 MHz) δ 9.46 (s, 2H), 7.26 (d, 2H, J= 8.10 Hz), pentylbenzamide 7.05 (d, 2H, J = 8.10 Hz), 6.98 (d, 4H, J =8.42 Hz), 6.66 (d, 4H, J = 8.28 Hz), 2.52-2.47 (m, 2H), 1.52-1.48 (m,2H), 1.28-1.21 (m, 4H), 0.83 (t, 3H, J = 7.00 Hz). MS m/z 376. 11q tansolid, 31% yield, M.p. 172-174° C. ¹H NMR (DMSO-d₆,N-(4-hydroxyphenyl)-4-pentyl- 300 MHz) δ 9.49 (s, 1H), 7.27 (d, 2H, J =8.06 Hz), 7.09 (d, N-(4-(2-(piperidin-1- 2H, J = 7.82 Hz), 7.05 (d, 2H,J = 8.30 Hz), 6.99 (d, 2H, J = 7.82 Hz), yl)ethoxy)phenyl)benzamide 6.86(d, 2H, J = 7.33 Hz), 6.66 (d, 2H, J = 7.33 Hz), 4.01 (bs, 2H), 3.33(bs, 4H), 2.64-2.63 (m, 2H), 2.51-2.36 (m, 2H), 1.53-1.51 (m, 6H), 1.37(bs, 2H), 1.27-1.23 (m, 4H), 0.83 (t, 3H, J = 7.20 Hz). MS m/z 488 (M +H)⁺. 11r tan solid, 80% yield, M.p. > 250° C. ¹H NMR (DMSO-d₆, 300 MHz)4-tert-butyl-N,N-bis(4- δ 9.48 (bs, 2H), 7.32-7.24 (m, 4H), 6.99 (d, 4H,J = 8.56 Hz), hydroxyphenyl)benzamide 6.67 (d, 4H, J = 8.44 Hz), 1.21(s, 9H). MS m/z 363. 11s tan solid, 39% yield, M.p. 208-210° C. ¹H NMR(DMSO-d₆, 4-tert-butyl-N-(4- 300 MHz) δ 9.50 (s, 1H), 7.34-7.25 (m, 4H),7.10 (d, 2H, J = 8.71 Hz), hydroxyphenyl)-N-(4-(2- 6.99 (d, 2H, J = 8.61Hz), 6.87 (d, 2H, J = 8.71 Hz), (piperidin-1- 6.67 (d, 2H, J = 8.61 Hz),4.02 (t, 2H, J = 5.70 Hz), 3.33 (bs, yl)ethoxy)phenyl)benzamide 2H),2.64 (bs, 2H), 2.43 (bs 2H), 1.50-1.47 (m, 4H), 1.38-1.36 (m, 2H), 1.21(s, 9H). MS m/z 473 (M + H)⁺. 11t yellow foam, M.p. 129-131° C. ¹H NMR((DMSO-d₆, 300 MHz) 3-{4-[Bis-(4-hydroxy-phenyl)- δ9.49 (s, 2H),7.61-7.56 (m, 3H), 7.39 (d, J = 8.26 Hz, carbamoyl]-phenyl}-acrylic acid2H), 7.04-7.02 (m, 4H), 6.66-6.61 (m, 5H), 3.71 (s, 3H), 1.53-1.52 (m,2H, CH₂), 0.82tJ = 7.33 Hz, 3H, CH₃). MS m/z 388.1 (M − H)⁻. 11upale-yellow foam, M.p. 122-124° C. ¹H NMR ((DMSO-d₆,3-{4-[Bis-(4-hydroxy-phenyl)- 300 MHz) δ9.51 (bs, 1H), 7.29 (d, J = 8.23Hz, 2H), carbamoyl]-phenyl}-propionic 7.13-7.08 (m, 4H), 6.99 (d, J =8.60 Hz, 2H), 6.85 (d, J = 8.60 Hz, acid 2H), 6.65 (d, J = 8.23 Hz, 2H),3.99 (q, J = 7.10, 14.21 Hz, 2H), 3.71 (s, 3H), 2.78 (t, J = 7.44 Hz,2H), 2.56 (t, J = 7.44 Hz, 2H), 1.11tJ = 7.06 Hz, 3H, CH₃). MS m/z 418.1(M − H)⁻. 11v pale-yellow foam, M.p. 122-124° C. ¹H NMR ((DMSO-d₆,N,N-Bis-(4-hydroxy-phenyl)-4- 300 MHz) δ9.51 (bs, 1H), 7.29 (d, J = 8.23Hz, 2H), (3-hydroxy-propyl)-benzamide 7.13-7.08 (m, 4H), 6.99 (d, J =8.60 Hz, 2H), 6.85 (d, J = 8.60 Hz, 2H), 6.65 (d, J = 8.23 Hz, 2H), 3.99(q, J = 7.10, 14.21 Hz, 2H), 3.71 (s, 3H), 2.78 (t, J = 7.44 Hz, 2H),2.56 (t, J = 7.44 Hz, 2H), 1.11tJ = 7.06 Hz, 3H CH₃). MS m/z 418.1 (M −H)⁻. 6a white solid. 49% yield. ¹H NMR (DMSO-d₆, 500 MHz) δ2-(N-(4-methoxyphenyl)-4- 7.69-7.68 (m, 2H), 7.46-7.45 (m, 2H),7.41-7.40 (m, 2H), methylphenylsulfonamido)ethyl 7.37-7.35 (m, 2H),6.79-6.77 (m, 2H), 6.72-6.70 (m, 2H), 4-methylbenzenesulfonate 3.91 (t,J = 5.0 Hz, 2H), 3.77 (t, J = 5.0 Hz, 2H), 3.72 (s, 3H), 2.43 (s, 3H),2.39 (s, 3H). MS m/z 498 (M + Na)⁺. 6b white solid, 63% yield. M.p.79.0-81.0° C. ¹H NMR (DMSO- (R)-3-bromo-2-hydroxy-N-(4- d₆, 500 MHz) δ9.47 (s, 1H), 7.65 (d, 2H, J = 9.0 Hz), methoxyphenyl)-2- 6.89 (d, 2H, J= 9.0 Hz), 6.12 (s, 1H), 3.81 (d, 1H, J = 10.2 Hz), methylpropanamide3.71 (s, 3H), 3.56 (d, 1H, J = 10.2 Hz), 1.45 (s, 3H). MS m/z 288 (M +H)⁺. 6c colorless oil, 39% yield. ¹H NMR (CDCl₃, 300 MHz) δ(S)-2-hydroxy-N,3-bis(4- 8.34 (s, 1H), 7.40 (d, 2H, J = 9.0 Hz), 7.16(d, 2H, J = 8.4 Hz), methoxyphenyl)-2- 6.86-6.83 (m, 4H), 3.79 (s, 3H),3.78 (s, 3H), 3.38 (d, 1H, J = 13.6 Hz), methylpropanamide 2.80 (d, 1H,J = 13.9 Hz), 1.53 (s, 3H). MS m/z 338 (M + Na)⁺. 6d white solid, 99%yield. M.p. 101.0-102.0° C. ¹H NMR (S)-2-hydroxy-3-(4- (CDCl₃, 300 MHz)δ 8.64 (s, 1H), 7.49 (d, 2H, J = 8.9 Hz), methoxyphenoxy)-N-(4-6.89-6.79 (m, 6H), 4.35 (d, 1H, J = 8.9 Hz), 3.93 (d, 1H, J = 8.9 Hz),methoxyphenyl)-2- 3.79 (s, 3H), 3.76 (s, 3H), 1.56 (s, 3H). MS m/zmethylpropanamide 254 (M + Na)⁺. 6e colorless oil, 98% yield. ¹H NMR(DMSO-d₆, 500 MHz) δ (R)-3-bromo-2-hydroxy-N-(4- 9.33 (s, 1H), 9.21 (s,1H), 7.47 (d, 2H, J = 8.9 Hz), 6.68 (d, 2H, hydroxyphenyl)-2- J = 9.0Hz), 6.08 (s, 1H), 3.80 (d, 1H, J = 10.3 Hz), 3.55 (d, methylpropanamide1H, J = 10.5 Hz), 1.44 (s, 3H). MS m/z 297 (M + Na)⁺. 6f colorless oil,67% yield. ¹H NMR (DMSO-d₆, 500 MHz) δ (S)-2-hydroxy-3-(4- 9.35 (s, 1H),9.19 (s, 1H), 8.90 (s, 1H), 7.48 (d, 2H, J = 8.8 Hz),hydroxyphenoxy)-N-(4- 6.73 (d, 2H, J = 9.0 Hz), 6.68 (d, 2H, J = 9.0Hz), hydroxyphenyl)-2- 6.63 (d, 2H, J = 9.0 Hz), 5.89 (s, 1H), 4.06 (d,1H, J = 9.5 Hz), methylpropanamide 3.81 (d, 1H, J = 9.3 Hz), 1.36 (s,3H). MS m/z 326 (M + Na)⁺. 6g colorless oil, 65% yield. ¹H NMR (DMSO-d₆,300 MHz) δ (S)-2-hydroxy-N,3-bis(4- 9.15 (s, 1H), 9.08 (s, 1H), 9.03 (s,1H), 7.34 (d, 2H, J = 9.0 Hz), hydroxyphenyl)-2- 6.97 (d, 2H, J = 8.4Hz), 6.64 (d, 2H, J = 8.9 Hz), methylpropanamide 6.58 (d, 2H, J = 8.4Hz), 5.50 (s, 1H), 2.90 (d, 1H, J = 13.5 Hz), 2.68 (d, 1H, J = 13.5 Hz),1.29 (s, 3H). MS m/z 310 (M + Na)⁺. 2a white solid, 98% yield. M.p.119.5-120° C. ¹H NMR 4-Methoxy-N,N-bis-(4- (CDCl₃, 300 MHz) δ 7.42 (d,2H, J = 8.9 Hz), 7.05 (d, 4H, J = 8.8 Hz), methoxyphenyl)-benzamide 6.81(d, 4H, J = 8.9 Hz), 6.71 (d, 2H, J = 8.9 Hz), 3.77 (s, 9H). MS m/z 364(M + H). 3a white solid, 79% yield. M.p. 275-276° C. (decomposed). ¹H4-Hydroxy-N,N-bis-(4- NMR (DMSO-d₆, 300 MHz) δ 9.79 (s, 1H), 9.44 (s,2H), hydroxyphenyl)-benzamide 7.21 (d, 2H, J = 9.0 Hz), 6.93 (d, 4H, J =8.7 Hz), 6.66 (d, 4H, J = 8.7 Hz), 6.58 (d, 2H, J = 9.0 Hz). MS m/z 344(M + Na)⁺. 2d white solid, 98% yield. M.p. 77-77.5° C. ¹H NMR (CDCl₃,N,N-Bis-(4-methoxyphenyl)- 300 MHz) δ 7.46-7.42 (m, 2H), 7.29-7.17 (m,3H), benzamide 7.09-7.06 (m, 4H), 6.81-6.78 (m, 4H), 3.76 (s, 6H). MSm/z 356 (M + Na)⁺. 3d white solid, 98% yield. M.p. >265° C.(decomposed). ¹H N,N-Bis-(4-hydroxyphenyl)- NMR (DMSO-d₆, 300 MHz) δ9.48 (s, 2H), 7.37-7.20 (m, benzamide 5H), 7.01 (d, 4H, J = 8.9 Hz),6.66 (d, 4H, J = 7.9 Hz), 6.58 (d, 2H, J = 7.3 Hz). MS m/e 304 (M − H)⁻.2g white solid, 89% yield. M.p. 178.4-179.3° C. ¹H NMRN,N-Diphenyl-benzamide (CDCl₃, 300 MHz) δ 7.46-7.44 (m, 2H), 7.28-7.23(m, 5H), 7.21-7.14 (m, 8H). MS m/z 296 (M + Na)⁺. 3e white solid, 57%yield. M.p. 193.7.0-194.3° C. ¹H NMR 4-Hydroxy-N,N-diphenyl- (DMSO-d₆,300 MHz) δ 9.89 (s, 1H), 7.35-7.13 (m, 12H), benzamide 6.59 (d, 2H, J =8.6 Hz). MS m/z 312 (M + Na)⁺. 2i white solid, 93% yield. M.p.103-105.9° C. ¹H NMR N-(3-methoxyphenyl)-N-phenyl- (CDCl₃, 300 MHz) δ7.49-7.45 (m, 2H), 7.31-7.15 (m, 9H), benzamide 6.75-6.70 (m, 3H), 3.76(s, 3H). MS m/z 326 (M + Na)⁺. 3h white solid, 56% yield. M.p.199.0-202.0° C. ¹H NMR N-(3-Hydroxyphenyl)-N-phenyl- (DMSO-d₆, 300 MHz)δ 9.55 (s, 1H), 7.44-7.06 (m, 12H), benzamide 6.62-6.59 (m, 2H). MS m/z312 (M + Na)⁺. 2j white solid, 78% yield. ¹H NMR (CDCl₃, 300 MHz) δ4-Methoxy-N-(4- 7.44-7.41 (m, 2H), 7.28-7.26 (m, 2H), 7.15-7.05 (m, 5H),methoxyphenyl)-N-phenyl- 6.83-6.80 (m, 2H), 6.72-6.70 (m, 2H), 3.77 (s,6H). MS m/z benzamide 356 (M + Na)⁺. 3i white solid, 55% yield. M.p.240.0-243.0° C. (decomposed). 4-Hydroxy-N-(4- ¹H NMR (DMSO-d₆, 300 MHz)δ 9.84 (s, 1H), 9.51 (s, 1H), hydroxyphenyl)-N-phenyl- 7.33-7.11 (m,7H), 6.97-6.94 (m, 2H), 6.69-6.67 (m, 2H), benzamide 6.61-6.58 (m, 2H).MS m/e 304 (M − H)⁻. 2h white solid, 95% yield. M.p. 153-154.2° C. ¹HNMR N-(4-methoxyphenyl)-N-phenyl- (CDCl₃, 300 MHz) δ 7.47-7.43 (m, 2H),7.30-7.02 (m, 8H), benzamide 6.83-6.78 (m, 2H), 3.76 (s, 3H). MS m/z 326(M + Na)⁺. 2k white solid, 84% yield. M.p. 119.0-119.5° C. ¹H NMR4-Methoxy-N-(3- (CDCl₃, 300 MHz) δ 7.47-7.43 (m, 2H), 7.31-7.13 (m, 7H),methoxyphenyl)-N-phenyl- 6.75-6.68 (m, 4H), 3.77 (s, 3H), 3.71 (s, 3H).MS m/z benzamide 356 (M + Na)⁺. 3g white solid, 70% yield. M.p.255.0-256.0° C. ¹H NMR N-(4-Hydroxyphenyl)-N-phenyl- (DMSO-d₆, 300 MHz)δ 9.53 (s, 1H), 7.40-7.15 (m, 10H), benzamide; 7.02 (d, 2H, J = 8.7 Hz),6.67 (d, 2H, J = 8.7 Hz). MS m/z 312 (M + Na)⁺. 3j white solid, 73%yield. M.p. 245.0-247.5° C. (decomposed). 4-Hydroxy-N-(3- ¹H NMR(DMSO-d₆, 300 MHz) δ 9.90 (s, 1H), 9.53 (s, 1H),hydroxyphenyl)-N-phenyl- 7.35-7.06 (m, 8H), 6.63-6.52 (m, 5H). MS m/e304 (M − H)⁻. benzamide; 4a yellow solid. 45% yield. M.p. 164.5-165.0°C. ¹H NMR N-(4-Hydroxyphenyl)-N-[4-(2- (DMSO-d₆, 300 MHz) δ 9.49 (s,1H), 7.38-7.36 (m, 2H), piperidin-1-ylethoxy)-phenyl]- 7.26-7.24 (m,3H), 7.12 (d, 2H, J = 8.5 Hz), 7.01 (d, 2H, J = 8.5 Hz), benzamide 6.87(d, 2H, J = 8.3 Hz), 6.65 (d, 2H, J = 8.3 Hz), 4.01 (t, 2H, J = 5.1 Hz),2.63 (br, 2H), 2.50-2.43 (m, 4H), 1.48 (br, 4H), 1.38-1.36 (m, 2H). MSm/z 417 (M + H)⁺. 3b white solid, 92% yield. M.p. 257.0-259.0° C. ¹H NMR3-Hydroxy-N-bis-(4- (DMSO-d₆, 300 MHz) δ 9.49 (s, 1H), 9.47 (s, 2H),hydroxyphenyl)-benzamide 7.02-6.98 (m, 5H), 6.80-6.65 (m, 7H). MS m/e320 (M − H)⁻. 3k off-white solid, 87% yield. M.p. 270.0-271.0° C. ¹H NMRN,N-Bis(4-hydroxyphenyl)-4- (DMSO-d₆, 300 MHz) δ 9.90 (s, 1H), 9.53 (s,1H), fluoro-benzamide 7.35-7.06 (m, 8H), 6.63-6.52 (m, 5H). MS m/e 304(M − H)⁻. 3f white solid, 85% yield. M.p. 152.5-153.2° C. ¹H NMR3-Hydroxy-N,N-diphenyl- (DMSO-d₆, 300 MHz) δ 9.89 (s, 1H), 7.35-7.13 (m,12H), benzamide 6.59 (d, 2H, J = 8.6 Hz). MS m/z 312 (M + Na)⁺. 3c whitesolid, 92% yield. M.p. 249.1° C. (decomposed). ¹H 4-Hydroxy-N-(4- NMR(DMSO-d₆, 300 MHz) δ 9.79 (s, 1H), 9.44 (s, 2H), hydroxyphenyl)-N-(3-7.21 (d, 2H, J = 9.0 Hz), 6.93 (d, 4H, J = 8.7 Hz), 6.66 (d, 4H, J = 8.7Hz), hydroxyphenyl)-benzamide 6.58 (d, 2H, J = 9.0 Hz). MS m/z 344 (M +Na). 4c yellow solid, 57% yield. M.p. 149.5-150.0° C. ¹H NMRN,N-diphenyl-[3-(2-piperidinyl- (DMSO-d₆, 300 MHz) δ 10.76 (s, 1H),7.33-6.92 (m, 14H), ethoxy)]-benzamide 4.32 (s, 2H), 3.42-3.40 (m, 4H),2.94-2.92 (m, 2H), hydrochloride 1.78-1.67 (m, 5H), 1.38 (br, 1H). MSm/z 401 (M + H)⁺. 4d yellow solid, 50% yield. M.p. 148.5-149.5° C. ¹HNMR N,N-diphenyl-[3-(2-piperidinyl- (DMSO-d₆, 300 MHz) δ 10.67 (s, 1H),7.40-6.85 (m, 14H), ethoxy)]-benzamide 4.38 (s, 2H), 3.48-3.41 (m, 4H),2.96-2.94 (m, 2H), hydrochloride 1.77-1.66 (m, 5H), 1.34 (br, 1H). MSm/z 401 (M + H)⁺. 3l white solid, 86% yield. M.p. 158.0-158.8° C. ¹H NMR4-Hydroxy-N,N-diphenyl- (CDCl₃, 300 MHz) δ 10.61 (s, 1H), 7.52-7.47 (m,2H), phenyl-sulfonamide 7.39-7.25 (m, 10H), 6.93-6.89 (m, 2H). MS m/z324 (M − H)⁻. 4e yellow solid, 38% yield. M.p. 183.7-185.0° C.(decomposed). N-(4-Hydroxyphenyl)-N-phenyl- ¹H NMR (DMSO-d₆, 300 MHz) δ10.76 (s, 1H), 9.66 (s, 1H), [4-(2-piperidin-1-ylethoxy)]- 7.35-6.61 (m,13H), 4.37 (m, 2H), 3.40 (m, 4H), 2.94 (m, benzamide hydrochloride 2H),1.76-1.65 (m, 5H), 1.34 (m, 1H). MS m/z 417 (M + H)⁺. 4u yellow solid,27% yield. M.p. 210.9-212.0° C. (decomposed).N-[4-(2-piperidin-1-ylethoxy)- ¹H NMR (DMSO-d₆, 300 MHz) δ 11.07 (s,2H), phenyl]-N-phenyl-[4-(2- 7.35-6.84 (m, 13H), 4.38 (m, 4H), 3.40 (br,8H), 2.95 (m, 4H), piperidin-1-ylethoxy)]- 2.05-1.65 (m, 10H), 1.34 (m,2H). MS m/z 528 (M + H)⁺. benzamide dihydrochloride 4b yellow solid, 89%yield. M.p. 138.3-139.5° C. ¹H NMR N-(phenyl)-N-[4-(2-piperidin-1-(DMSO-d₆, 300 MHz) δ 9.52 (s, 1H), 7.42-7.39 (m, 2H),ylethoxy)-phenyl]-benzamide 7.33-7.16 (m, 10H), 6.89-6.91 (m, 2H), 4.17(s, 2H), 2.76 (s, hydrochloride 2H), 2.51-2.49 (m, 4H), 1.61 (br, 4H),1.43 (br, 2H). MS m/z 401 (M + H)⁺. 3m white solid, 90% yield. M.p.246.3-247.0° C. ¹H NMR 4-Hydroxy-N-(4- (DMSO-d₆, 300 MHz) δ 9.84 (s,1H), 9.53 (s, 1H), hydroxyphenyl)-N-(4- 7.24-7.13 (m, 6H), 6.98-6.95 (m,2H), 6.69-6.67 (m, 2H), 6.69-6.66 (m, fluorophenyl)-benzamide 2H),6.61-6.58 (m, 2H). MS m/z 324 (M + H)⁺. 4f pale-yellow solid. 79% yield.M.p. 211.6-212.5° C. ¹H NMR N,N-diphenyl-bis[4-(2-piperidin- (DMSO-d₆,300 MHz) δ 10.78 (s, 1H), 7.65-7.17 (m, 14H),1-ylethoxy)-phenyl]-sulfonamide 4.52 (m, 2H), 3.36-3.47 (m, 4H), 3.00(br, 2H), 1.67-2.50 (m, hydrochloride 5H), 1.38 (m, 1H). MS m/z 437 (M +H)⁺. 4g pale-yellow solid, 45% yield. M.p. 168.3-169.0° C. ¹H NMRN-(4-Fluorophenyl)-N-[4- (DMSO-d₆, 500 MHz) δ 10.61 (s, 1H), 9.65 (s,1H), hydroxyphenyl]-[4-(2-piperidin- 7.38-6.69 (m, 12H), 4.38 (m, 2H),3.46-3.36 (m, 4H), 2.96 (m, 2H), 1-ylethoxy)]-benzamide 2.04-1.66 (m,5H), 1.35 (br, 1H). MS m/z 435 (M + H)⁺. 4r yellow solid, 95% yield.M.p. 253.5-254.0° C. (decomposed). N-(4-Fluorophenyl)-N-[4-(2- ¹H NMR(DMSO-d₆, 300 MHz) δ 11.03 (s, 2H), piperidin-1-ylethoxy)-phenyl]-[4-7.42-7.39 (m, 2H), 7.28-7.26 (m, 3H), 7.20-7.17 (m, 4H), 6.94-6.92 (m,(2-piperidin-1-yl-ethoxy)]- 4H), 4.39 (br, 4H), 3.46-3.42 (m, 8H),3.01-2.94 (m, 4H), benzamide dihydrochloride 1.85-1.65 (m, 10H),1.38-1.34 (m, 2H). MS m/z 528 (M + H)⁺. 4h yellow solid, 42% yield. M.p.234.0-235.8° C. (decomposed). N-(4-Hydroxyphenyl)-N-[4-(2- ¹H NMR(DMSO-d₆, 300 MHz) δ 10.85 (s, 1H), 9.65 (s, 1H),piperidin-1-ylethoxy)-phenyl]-4- 7.42-6.68 (m, 12H), 4.38 (m, 2H), 3.40(m, 4H), 2.95 (m, fluoro-benzamide hydrochloride 2H), 2.06-1.77 (m, 5H),1.35 (m, 1H). MS m/z 435 (M + H)⁺. 4s yellow solid, 20% yield. M.p.204.8-205.5° C. (decomposed). N,N-Bis[4-(2-piperidin-1- ¹H NMR (DMSO-d₆,300 MHz) δ 11.01 (s, 2H), ylethoxy)-phenyl]-4-fluoro- 7.45-6.92 (m,12H), 4.38 (m, 4H), 3.38 (m, 8H), 2.95 (m, 4H), benzamidedihydrochloride; 2.06-1.67 (m, 10H), 1.35 (m, 2H). MS m/z 546 (M + H)⁺.3n white solid, 86% yield. M.p. 215.7° C. (decomposed). ¹HN,N-Bis(4-hydroxyphenyl)-1- NMR (DMSO-d₆, 500 MHz) δ 9.54 (s, 1H), 9.35(s, 1H), naphthylamide; (3n) 8.11 (d, 1H, J = 9.0 Hz), 8.87 (d, 1H, J =8.0 Hz), 7.79 (d, 1H, J = 8.5 Hz), 7.61-7.58 (m, 1H), 7.53-7.48 (m, 2H),7.37-7.34 (m, 1H), 7.30 (s, 2H), 7.00 (s, 2H), 6.83 (s, 2H), 6.38 (s,2H). MS m/z 356 (M + H)⁺. 4t yellow solid, 28% yield. M.p. 218.6-219.5°C. (decomposed). N,N-Bis[4-(2-piperidin-1- ¹H NMR (DMSO-d₆, 300 MHz) δ11.09 (s, 2H), ylethoxy)-phenyl]-benzamide 7.38-6.86 (m, 12H), 4.40 (m,4H), 3.39 (m, 8H), 2.96 (m, 4H), dihydrochloride; (4t) 2.07-1.66 (m,10H), 1.35 (m, 2H). MS m/z 546 (M + H)⁺. 3o white solid, 84% yield.M.p. >300° C. (decomposed). ¹H 4-Hydroxy-N-(1-Naphthyl)-N-(4- NMR(DMSO-d₆, 300 MHz) δ 9.84 (s, 1H), 9.47 (s, 1H),hydroxyphenyl)-benzamide 8.07 (d, 1H, J = 7.8 Hz), 7.97 (d, 1H, J = 7.8Hz), 7.86 (d, 1H, J = 8.1 Hz), 7.58-7.45 (m, 3H), 7.39-7.30 (m, 3H),7.02 (d, 2H, J = 8.1 Hz), 6.66-6.56 (m, 4H). MS m/e 354 (M − H)⁻. 5awhite solid. 93% yield. M.p. 237.5-238.9° C. ¹H NMR4-Chloro-N-[4-hydroxyphenyl]- (DMSO-d₆, 300 MHz) δ 9.53 (s, 1H),7.41-7.38 (m, 2H), N-(4-methoxyphenyl)- 7.34-7.31 (m, 2H), 7.17-7.14 (m,2H), 7.05-7.02 (m, 2H), benzamide 6.88-6.86 (m, 2H), 6.70-6.66 (m, 2H),3.71 (s, 3H). MS m/z 354 (M + H)⁺. 5b white solid. 71% yield. M.p.182-182.9° C. ¹H NMR 4-Cyano-N-[4-hydroxyphenyl]- (DMSO-d₆, 300 MHz) δ9.56 (s, 1H), 7.76-7.71 (m, 2H), N-(4-methoxyphenyl)- 7.56-7.55 (m, 2H),7.20 (br, 2H), 7.07 (br, 2H), 6.87 (br, 2H), benzamide 6.67 (br, 2H),3.71 (s, 3H). MS m/z 345 (M + H)⁺. 4j colorless oil, 61% yield. M.p. C.¹H NMR (DMSO-d₆, 300 MHz) 4-Cyano-N-[4-(2-piperidin-1- δ 7.42-7.40 (m,2H), 7.34-7.31 (m, 2H), 7.18-7.13 (m, ylethoxy)-phenyl]-N-(4- 4H),6.88-6.86 (m, 4H), 4.00 (tr, 2H, J = 5.7 Hz), 3.71 (s,methoxyphenyl)-benzamide 3H). 2.60 (tr, 2H, J = 5.7 Hz), 2.40 (br, 4H),1.47-1.45 (m, 4H), 1.37-1.36 (m, 2H). MS m/z 465 (M + H)⁺. 5c whitesolid. 74% yield. M.p. C. ¹H NMR (DMSO-d₆, 300 MHz)3-Chloro-N-[4-hydroxyphenyl]- δ 9.53 (s, 1H), 7.45-7.44 (m, 1H),7.36-7.24 (m, 3H), N-(4-methoxyphenyl)- 7.20-7.18 (m, 2H), 7.08-7.05 (m,2H), 6.89 (br, 2H), 6.69 (br, benzamide 2H), 3.71 (s, 3H). MS m/z 354(M + H)⁺. 4i yellow solid. 47% yield. M.p. 293.9-295.0° C. (decomposed).3-(2-piperidin-1-ylethoxy)-N,N- ¹H NMR (DMSO-d₆, 300 MHz) δ 10.51 (s,2H), bis(4-hydroxyphenyl)- 8.18-7.68 (m, 12H), 4.00 (tr, 2H, J = 5.5Hz), 2.62 (m, 2H), 2.41 (m, benzamide 4H), 1.50-1.46 (m, 4H), 1.37-1.35(m, 2H). MS m/e 431 (M − H)⁻. 4k white solid, 45% yield. M.p.285.0-287.0° C. (decomposed). 4-Chloro-N-[4-(2-piperidin-1- ¹H NMR(DMSO-d₆, 300 MHz) δ 9.55 (s, 1H), 7.40-7.39 (m, ylethoxy)-phenyl]-N-(4-2H), 7.34-7.32 (m, 2H), 7.20 (br, 2H), 7.02 (br, 2H), 6.95 (br,methoxyphenyl)-benzamide 2H), 6.68-6.67 (m, 2H), 4.28 (m, 2H), 3.34 (br,4H), 2.99 (m, 2H), 1.72 (br, 4H), 1.46 (br, 2H). MS m/z 451 (M + H)⁺. 4lyellow solid, 75% yield. M.p. 118.1-118.5° C. ¹H NMR4-Cyano-N-[4-(2-piperidin-1- (DMSO-d₆, 300 MHz) δ 7.51 (br, 4H), 7.05(br, 4H), 6.82 (br, ylethoxy)-phenyl]-N-(4- 4H), 4.10 (m, 2H), 3.78 (s,3H), 2.81 (m, 2H), 2.56 (m, 4H), methoxyphenyl)-benzamide 1.64-1.62 (m,4H), 1.48-1.46 (m, 2H). MS m/z 456 (M + H)⁺. 4m yellow solid, 82% yield.M.p. 114.9-115.5° C. ¹H NMR 3-Chloro-N-[4-(2-piperidin-1- (DMSO-d₆, 300MHz) δ 7.47-7.46 (m, 1H), 7.26-7.23 (m, ylethoxy)-phenyl]-N-(4- 2H),7.14-7.05 (m, 5H), 6.83-6.80 (m, 4H), 4.08 (tr, 2H, J = 6.0 Hz),methoxyphenyl)-benzamide 3.77 (s, 3H), 2.76 (tr, 2H, J = 6.0 Hz),2.53-2.49 (m, 4H), 1.65-1.58 (m, 4H), 1.48-1.43 (m, 2H). MS m/z 465 (M +H)⁺. 7a yellow solid. 65% yield. M.p. 217.0-218.5° C. (decomposed).5-[4-methoxy-phenyl]-5H- ¹H NMR (DMSO-d₆, 500 MHz) δ 8.61-8.59 (m, 1H),phenanthridin-6-one 8.54-8.51 (m, 1H), 8.36-8.34 (m, 1H), 7.94-7.89 (m,1H), 7.71-7.66 (m, 1H), 7.43-7.28 (m, 4H), 7.19-7.16 (m, 2H), 6.63-6.60(m, 1H). MS m/z 302 (M + H)⁺. 3p white solid, 84% yield. M.p.272.0-273.5° C. (decomposed). 4-Cyano-N,N-Bis(4- ¹H NMR (DMSO-d₆, 300MHz) δ 9.53 (s, 2H), 7.74-7.73 (m, hydroxyphenyl)-benzamide 2H),7.55-7.53 (m, 2H), 7.12-7.02 (m, 4H), 6.74-6.57 (m, 4H). MS m/e 329 (M −H)⁻. 7b yellow solid. 78% yield. M.p. 325.7-327.0° C.5-[4-hydroxy-phenyl]-5H- (decomposed). ¹H NMR (DMSO-d₆, 500 MHz) δ 9.82(s, phenanthridin-6-one 1H), 8.60-8.58 (m, 1H), 8.52-8.51 (m, 1H),8.35-8.33 (m, 1H), 7.92-7.89 (m, 1H), 7.69-7.66 (m, 1H), 7.41-7.38 (m,1H), 7.32-7.29 (m, 1H), 7.15-7.13 (m, 2H), 6.99-6.97 (m, 2H), 6.65-6.63(m, 1H). MS m/z 310 (M + Na)⁺. 3q white solid, 84% yield. M.p.237.5-238.0° C. ¹H NMR 3-Cyano-N,N-Bis(4- (DMSO-d₆, 300 MHz) δ 9.53 (s,2H), 7.81-7.80 (m, 1H), hydroxyphenyl)-benzamide 7.75-7.74 (m, 1H),7.73-7.72 (m, 1H), 7.69-7.68 (m, 1H), 7.67-7.7.66 (m, 1H), 7.48-7.44 (m,1H), 7.07 (br, 4H), 6.65 (br, 4H). MS m/z 353 (M + Na)⁺. 7c yellowsolid. 79% yield. M.p. 220.0-221.5° C. (decomposed).5-[4-(2-piperidin-1-ylethoxy)- ¹H NMR (DMSO-d₆, 300 MHz) δ 8.56-8.53 (m,1H), phenyl]-5H-phenanthridin-6-one 8.35-8.29 (m, 2H), 7.84-7.79 (m,1H), 7.64-7.59 (m, 1H), 7.36-7.24 (m, 4H), 7.23-7.10 (m, 2H), 6.76-6.73(m, 1H), 4.45 (tr, 2H, J = 5.1 Hz), 3.16 (tr, 2H, J = 5.1 Hz), 2.94 (br,4H), 1.90-1.85 (m, 4H), 1.61-1.59 (m, 2H). MS m/z 399 (M + H)⁺. 8b whitesolid, 86% yield. M.p. 265.1-266.2° C. (decomposed).Cyclohexane-carboxylic acid ¹H NMR (DMSO-d₆, 500 MHz) δ 9.65 (s, 1H),9.37 (s, 1H), bis(4-hydroxyphenyl)-amide; 7.17-6.70 (m, 4H), 6.78-6.67(m, 4H), 2.29-2.23 (m, 1H), 1.71-1.62 (m, 4H), 1.54-1.51 (m, 1H),1.41-1.32 (m, 2H), 1.21-1.07 (m, 1H), 0.97-0.90 (m, 2H). MS m/z 334 (M +Na)⁺. 3r white solid, 86% yield. M.p. 264.3-265.2° C. (decomposed).N,N-Bis(4-hydroxyphenyl)-2- ¹H NMR (DMSO-d₆, 500 MHz) δ 9.46 (s, 2H),7.98 (s, 1H), naphthylamide 7.85-7.75 (m, 2H), 7.75-7.73 (m, 2H),7.54-7.48 (m, 2H), 7.45-7.43 (m, 1H), 7.05 (s, 4H), 6.66 (s, 4H). MS m/z356 (M + H)⁺. 3s white solid, 50% yield. M.p. 266.7-268.0 (decomposed).¹H 4-Cyano-N-[4-(2-piperidin-1- NMR (DMSO-d₆, 300 MHz) δ 9.57 (s, 1H),7.76-7.74 (m, ylethoxy)-phenyl]-N-(4- 2H), 7.58-7.55 (m, 2H), 7.24-6.96(m, 6H), 6.66 (s, 2H), hydroxyphenyl)-benzamide 4.26-4.21 (m, 2H), 3.33(br, 4H). 2.98 (br, 2H), 1.70 (br, 4H), 1.50-1.44 (m, 2H). MS m/z 442(M + H)⁺. 3t white solid, 38% yield. M.p. 208.9-209.5° C. (decomposed).3-Chloro-N-[4-(2-piperidin-1- ¹H NMR (DMSO-d₆, 300 MHz) δ 9.54 (s, 1H),7.44 (s, 1H), ylethoxy)-phenyl]-N-(4- 7.37-7.21 (m, 5H), 7.08-7.05 (m,2H), 6.96 (s, 2H), hydroxyphenyl)-benzamide 6.69-6.67 (s, 2H), 4.27 (s,2H), 3.33 (br, 4H). 3.02 (br, 2H), 1.71 (br, 4H), 1.50 (br, 2H). MS m/z451 (M + H)⁺. 10w white solid. 81% yield. M.p. 267.3-268.5° C. ¹H NMRN-cyclohexyl-4-hydroxy-N-(4- (DMSO-d₆, 500 MHz) δ 9.56 (s, 2H), 7.03 (d,2H, J = 8.7 Hz), hydroxyphenyl)-benzamide 6.83 (d, 2H, J = 8.8 Hz), 6.60(d, 2H, J = 8.5 Hz), 6.50 (d, 2H, J = 8.3 Hz), 4.43 (m, 1H), 1.83-1.81(m, 2H), 1.72-1.69 (m, 2H), 1.54-1.52 (m, 1H), 1.35-1.28 (m, 2H),1.11-1.03 (m, 2H), 0.93-0.89 (m, 1H). MS m/z 312 (M + H)⁺. 10x yellowoil. 92% yield. ¹H NMR (DMSO-d₆, 500 MHz) δ 4-((4-Fluorophenyl)(4- 9.29(s, 1H), 9.24 (s, 1H), 7.09 (d, 2H, J = 8.3 Hz), 6.98 (d, 2H, J = 9.0Hz), hydroxybenzyl)-amino)phenol 6.94-6.91 (m, 2H), 6.73 (d, 2H, J = 9.0Hz), 6.68-6.64 (m, 4H), 4.70 (s, 2H). MS m/z 308 (M − H)⁻. 10y whitesolid. 57% yield. M.p. 170.0-172.0° C. ¹H NMR N-(4-(2- (DMSO-d₆, 500MHz) δ 9.50 (s, 1H), 7.37 (d, 2H, J = 8.0 Hz),(dimethylamino)ethoxy)phenyl)- 7.29-7.24 (m, 3H), 7.12 (d, 2H, J = 6.5Hz), 7.01 (d, 2H, N-(4-hydroxy-phenyl)- J = 6.5 Hz), 6.87 (s, 2H), 6.66(s, 2H), 3.99 (s, 2H), 2.61 (t, benzamide 2H, J = 5.5 Hz), 2.21 (s, 6H).MS m/z 375 (M − H)⁻. 10z pale-yellow solid. 63% yield. M.p. 160.7-162.3°C. ¹H NMR 3-Cyano-N-(4-hydroxyphenyl)- (DMSO-d₆, 500 MHz) δ 9.56 (s,1H), 7.83 (s, 1H), N-(4-(2-(piperidin-1- 7.76-7.74 (m, 1H), 7.71-7.68(m, 1H), 7.47 (t, 1H, J = 7.5 Hz), 7.19 (br,yl)ethoxy)phenyl)-benzamide; 2H), 7.08 (br, 2H), 6.90 (br, 2H), 6.66(br, 2H), 4.02 (br, 2H), 2.63 (br, 2H), 2.42 (br, 4H), 1.48 (br, 4H),1.36 (br, 2H). MS m/z 442 (M + H)⁺. 11a white solid. 64% yield. M.p.163.9-165.1° C. ¹H NMR N-(4-Hydroxyphenyl)-N-(4-(2- (DMSO-d₆, 500 MHz) δ9.63 (s, 1H), 7.39-7.38 (m, 2H), (pyrrolidin-1-yl)ethoxy)phenyl)-7.31-7.23 (m, 3H), 7.13 (d, 2H, J = 6.0 Hz), 7.02 (d, 2H, J = 7.0 Hz),benzamide 6.88 (br, 2H), 4.03 (br, 2H), 2.82 (br, 2H), 2.56 (br, 4H),1.69-1.68 (m, 4H). MS m/z 401 (M − H)⁻. 11b white solid. 96% yield. M.p.255.9-256.5° C. ¹H NMR N,N-Bis(4-hydroxyphenyl)-4- (DMSO-d₆, 500 MHz) δ9.52 (s, 2H), 7.64-7.56 (m, 4H), (trifluoromethyl)-benzamide; 7.06 (br,4H), 6.64 (br, 4H). MS m/z 374 (M + H)⁺. 11c white solid. 41% yield.M.p. 158.1-158.7° C. ¹H NMR N-(4-Hydroxyphenyl)-N-(4-(2- (DMSO-d₆, 500MHz) δ 9.55 (s, 1H), 7.65-7.58 (m, 4H),(piperidin-1-yl)ethoxy)phenyl)-4- 7.18-6.65 (m, 8H), 4.01 (br, 1H),2.63-2.61 (m, 2H), (trifluoromethyl)-benzamide; 2.40-2.36 (m, 4H), 1.47(br, 4H), 1.36 (br, 2H). MS m/z 485 (M + H)⁺. 11d white solid. 92%yield. M.p. 216.0-217.0° C. (decomposed). N,N-Bis(4-hydroxyphenyl)-4- ¹HNMR (DMSO-d₆, 500 MHz) δ 9.55 (s, 2H), 8.11-8.09 (m, nitro-benzamide2H), 7.65-7.62 (m, 2H), 7.15-7.03 (m, 4H), 6.77-6.58 (m, 4H). MS m/z 349(M − H)⁻. 11e white solid. 87% yield. M.p. 254.1.1-254.6° C. ¹H NMR3-Fluoro-N,N-bis(4- (DMSO-d₆, 500 MHz) δ 9.51 (s, 2H), 7.31-7.26 (m,1H), hydroxyphenyl)-benzamide 7.19-7.18 (m, 2H), 7.13-7.09 (m, 1H), 7.05(br, 4H), 6.68 (br, 4H). MS m/z 322 (M − H)⁻. 11f white solid. 71%yield. M.p. 198.5-199.1° C. ¹H NMR N-(4-Hydroxyphenyl)-N-(4-(2-(DMSO-d₆, 500 MHz) δ 9.56 (s, 0.5H), 9.40 (s, 0.5H),(piperidin-1-yl)ethoxy)phenyl)-1- 8.13-8.10 (m, 1H), 7.89-7.78 (m, 2H),7.63-7.58 (m, 1H), naphthamide 7.54-7.49 (m, 2H), 7.38-7.30 (m, 3H),7.00 (br, 3H), 6.83 (br, 1H), 6.61 (br, 1H), 6.40 (br, 1H), 4.17-3.92(m, 2H), 2.73-2.44 (m, 6H), 1.55-1.41 (m, 6H). MS m/z 467 (M + H)⁺. 11gwhite solid. 53% yield. M.p. 227.3-228.0° C. ¹H NMR3-Fluoro-N-(4-hydroxyphenyl)- (DMSO-d₆, 500 MHz) δ 9.56 (s, 1H),7.33-7.26 (m, 1H), N-(4-(2-(piperidin-1- 7.21-7.12 (m, 5H), 7.09-7.04(m, 2H), 6.89 (br, 2H), 4.05 (br, yl)ethoxy)phenyl)benzamide 2H), 2.71(br, 2H), 2.50 (br, 4H), 1.93 (br, 2H), 1.51-1.49 (m, 4H), 1.39-1.37(br, 2H). MS m/z 435 (M + H)⁺. 11h yellow solid. 49% yield. M.p.181.7-182.3° C. ¹H NMR N-(4-Hydroxyphenyl)-4-nitro-N- (DMSO-d₆, 300 MHz)δ 9.55 (s, 1H), 8.07 (d, 2H, J = 8.7 Hz), (4-(2-(piperidin-1- 7.62 (d,2H, J = 8.7 Hz), 7.18-6.90 (m, 4H), yl)ethoxy)phenyl)benzamide 6.77-6.61(m, 4H), 4.01 (br, 2H), 2.64-2.43 (m, 6H), 1.46-1.35 (m, 6H). MS m/z 462(M + H)⁺. 11i white solid. 48% yield. M.p. 305.4° C. (decomposed). ¹HN,N-Bis(4-hydroxyphenyl)-4- NMR (DMSO-d₆, 300 MHz) δ 9.45 (s, 2H),8.14-8.10 (m, methoxy-1-naphthamide 2H), 7.65-7.60 (m, 1H), 7.54-7.49(m, 1H), 7.44-7.41 (m, 1H), 7.11 (br, 4H), 6.84-6.81 (m, 1H), 6.70-6.65(m, 4H), 3.93 (s, 3H). MS m/z 386 (M + H)⁺. 11j white solid. 45.0%yield. M.p. 195.8-196.3° C. ¹H NMR N-(4-Hydroxyphenyl)-N-(4-(2-(DMSO-d₆, 300 MHz) δ 9.49 (s, 1H), 8.01 (s, 1H),(piperidin-1-yl)ethoxy)phenyl)-2- 7.87-7.84 (m, 2H), 7.77-7.74 (m, 1H),7.56-7.43 (m, 3H), 7.19-7.16 (m, naphthamide 2H), 7.08-7.06 (m, 2H),6.88-6.85 (m, 2H), 6.67-6.65 (m, 2H), 3.99 (s, 2H), 2.61-2.57 (m, 2H),2.39 (s, 4H), 1.46-1.45 (m, 4H), 1.37-1.35 (m, 2H). MS m/z 467 (M + H)⁺.11k white solid. 78% yield. M.p. 292.0-294.0° C. ¹H NMR2-Hydroxy-N,N,2-tris(4- (DMSO-d₆, 300 MHz) δ 9.74 (s, 1H), 9.39 (s, 1H),9.15 (s, hydroxyphenyl)-propanamide 1H), 7.18 (d, 2H, J = 8.7 Hz), 7.09(d, 2H, J = 8.7 Hz), 6.80 (d, 2H, J = 8.7 Hz), 6.72 (d, 2H, J = 8.7 Hz),6.60 (d, 2H, J = 9.1 Hz), 6.53 (d, 2H, J = 9.1 Hz), 1.68 (s, 3H). MS m/z348 (M − H₂O)⁺. 11w pale-yellow solid, M.p. 145-147° C. ¹H NMR((DMSO-d₆, N-(4-hydroxyphenyl)-4-(3- 300 MHz) δ 9.50 bs, 1H), 7.28 (0(d, J = 8.10 Hz, 2H), hydroxypropyl)-N-(4-methoxyphenyl)- 7.15-7.05 (m,4H), 6.99 (d, J = 8.62 Hz, 2H), 6.86 (d, J = 8.74 Hz, benzamide 2H),6.66 (d, J = 8.56 Hz, 2H), 4.44 (bs, 1H), 3.71 (s, 3H), 3.35-3.33 (m,2H), 2.57-2.49 (m, 2H), 1.69-1.60 (m, 2H). MS m/z 376.0 (M − H)⁻. 11xcolorless oil. ¹H NMR ((DMSO-d₆, 300 MHz) δ7.29 (d, J = 8.13 Hz,4-fluoro-N,N-bis(4- 2H), 7.13-7.09 (m, 4H), 7.00 (d, J = 8.61 Hz, 2H),hydroxyphenyl)-2- 6.86 (d, J = 8.70 Hz, 2H), 6.66 (d, J = 8.49 Hz, 2H),3.71 (s, (trifluoromethyl)-benzamide 3H), 2.76 (t, J = 7.43 Hz, 2H),2.51-2.45 (m, 2H). MS m/z 390.0 (M − H)⁻. 11y M.p. 110-112° C. MS m/z364.1 (M + Na)⁺. ¹H NMR 3-fluoro-N-(4-fluorophenyl)-4- ((DMSO-d₆, 300MHz) δ 10.14 (bs, 1H), 9.71 (bs, 1H), hydroxy-N-(4- 7.25-7.11 (m, 5H),7.05-6.99 (m, 3H), 6.78 (t, J = 8.61 Hz, 2H), hydroxyphenyl)benzamide6.68 (d, J = 8.68 Hz, 2H). 11z M.p.135-137° C. MS m/z 431.3 (M + H)⁺. ¹HNMR ((DMSO- N-(4-hydroxyphenyl)-4-methyl- d₆, 300 MHz) δ 9.49 (bs, 1H),7.26 (d, J = 8.06 Hz, 2H), N-(4-(2-(piperidin-1- 7.11-6.98 (m, 6H), 6.85(d, J = 8.72 Hz, 2H), 6.66 (d, J = 8.53 Hz, yl)ethoxy)phenyl)benzamide2H), 4.00 (t, J = 5.85 Hz, 2H), 2.60 (t, J = 5.85 Hz, 2H), 2.41-2.38 (m,4H), 1.51-1.44 (m, 4H), 1.37-1.36 (m, 2H). 11aa M.p. > 240° C. MS m/z304.9 (M − H)⁻. ¹H NMR ((DMSO-d₆, N,N-bis(4-hydroxyphenyl)- 300 MHz) δ9.54 (bs, 2H), 8.52-8.43 (m, 2H), 7.76-7.72 (m, isonicotin-amide 1H),7.31-7.27 (m, 1H), 7.07 (bs, 4H), 6.68 (bs, 4H). 11ab MS m/z 418.4 (M +H)⁺. ¹H NMR ((DMSO-d₆, 300 MHz) δ (s, N-(4-hydroxyphenyl)-N-(4-(2- 1H),8.53 (d, 9.56 J = 1.65 Hz, 1H), 8.44 (dd, J = 1.61, 4.83 Hz,(piperidin-1-yl) 1H), 7.78-7.74 (m, 1H), 7.31-7.27 (m, 1H), 6.89 (bs,2H), ethoxy)phenyl)-isonicotinamide 6.68 (bs, 2H), 4.02 (t, J = 7.03 Hz,2H), 2.64 (bs, 2H), 2.43 (bs, 4H), 1.49-1.47 (m, 4H), 1.38-1.36 (m, 2H).

Example 2 Effects of SERMs on ER-α, ER-β and AR TransactivationMaterials and Methods

COS or 293 cells were plated in DME without phenol red+10% cs FBS at90,000 cells per well in 24 well plates, and were transfected with 0.25μg of the vector “ERE-LUC”, where a firefly luciferase gene is driven bytwo estrogen responsive elements and 0.02 μg of the control CMV-LUC,Renilla where a luciferase gene is driven by a CMV promoter. Also 25 ngof ER-α (FIGS. 1, 5, and 9), 50 ng of ERβ (FIGS. 2, 6 and 10) or 12.5 ngof AR (FIG. 3) were introduced by lipofectamine. All the receptors werecloned from rat tissue into the PCR3.1 vector backbone. Twenty fourhours post transfection, cells were treated with 4a, toremifene, 4h,estrogen, DHT, and other SERMs or combinations thereof, as indicated infigures. Cells were harvested 48 hrs after transfection, and assayed forfirefly and Renilla luciferase activity.

Results

Treating cells with either 4a or toremifene alone had no effect on ER-αactivity, under the tested conditions. However, both the compoundsinhibited the estradiol (E₂) induced ER-α activity to basal levels,suggesting that 4a can regulate ER activity, or function as a SERM, andin this assay functions as an ER-α antagonist.

In order to determine whether the compounds can function as agonists ofthe ER, COS or 293 cells expressing constructs with luciferaseexpression under the control of an ERE were incubated with estrogen,toremifene or 4a. While estrogen addition resulted in dose-dependentluciferase expression, neither SERM alone showed any such effect.Similarly, 4h was evaluated for expression of luciferase (FIGS. 5 a, band c).

Both 4a and 4h inhibited estrogen stimulated luciferase expression,indicating these compounds may function as SERMs in these circumstances,for example, as estrogen receptor α-antagonists. Compound 10o alsoinhibited estrogen stimulated luciferase expression, in 293 cellsexpressing ER-α similarly evaluated (FIG. 5 d,e).

COS or 293 cells expressing ER-β (FIGS. 2 and 6) were similarlyevaluated. Under these experimental conditions, neither 4a nor 4hstimulated LUC expression, and each inhibited E₂-stimulated LUCexpression, indicating their activity as antagonists for ER-β as well.

Under the tested conditions, compound 4a was specific for the ER, sincethe compound had no effect on LUC expression in COS cells expressing anandrogen receptor (AR), nor did it inhibit DHT-induced AR activation(FIG. 3).

Additional SERMs were similarly tested for their ability to mediateestrogen receptor signaling in the indicated conditions (FIG. 9). Of theSERMs tested, compounds 3e and 3i were the most potent in stimulatingER-α, and compounds 3a, 3e, 3i and 3g were most potent in stimulatingER-β (FIG. 10).

Example 3 Agonist Activity of Some Embodiments of the CompoundsMaterials and Methods

MCF-7 cells were plated at 500,000 cells per well of a 6 well plate. Thecells were serum starved for 3 days and then were treated as above for16 hrs. RNA was isolated and gene expression levels assessed by realtimeRT-PCR, following normalization to 18S ribosomal RNA.

Results

While estrogen increased pS2 (gene encoding the trefoil peptides)expression in MCF-7 cells under the conditions tested, 4a only minimallydid so, moreover, it inhibited estrogen-induced upregulation of pS2 geneexpression, indicating its role as a partial agonist or antagonist inthese conditions (FIG. 4). Compounds 3e, 3f and 3l increased pS2expression levels as well (FIG. 11).

Example 4 Effect of the Compounds on TRAP Positive MultinucleatedOsteoclasts Materials and Methods

Bone marrow cells isolated from rat femur were cultured in Alpha MEMwithout phenol red+10% sterile FBS without phenol red in the presence orabsence of 30 ng/mL RANKL and 10 ng/ml GMCSF. The cells were treated for12 days were stained for tartarate resistant acid phosphatase activity(TRAP) positive multinucleated osteoclasts and were counted.

Results

The administration of GMCSF and RANKL to pluripotent bone marrowprogenitors favors their differentiation to osteoclasts. The presence ofestrogen strongly suppressed osteoclast differentiation, while theadministration of 4a, 4h, and toremifene under these conditions,minimally but dose-dependently suppressed the osteoclast differentiation(FIG. 7).

Compound 3e was highly suppressive of osteoclast activity and stimulatedosteoblast activity, 3a suppressed osteoclasts, 3d stimulatedosteoblasts and suppressed osteoclasts (FIG. 14) and 4h was highlysuppressive of osteoclast activity under the tested conditions.

Example 5 The Compounds Inhibit Androgen Independent Prostate CancerCell Growth Materials and Methods

The prostate cancer cell line PC-3 was plated in RPMI+10% csFBS at 6000cells per well of a 96 well plate. Medium was changed to RPMI+1% csFBSwithout phenol red and cells were treated for 72 hrs with increasingconcentrations of SERMs.

Results

Compounds 4r, 4u and toremifene all inhibited PC-3 cell growth by 100%at 10 μM concentrations. Compound 4h, however, under the same conditionsinhibited PC-3 cell growth by 75% even at 1 μM concentration. Compound4a partially inhibited growth by about 50% (FIG. 8). PC-3 growthinhibition was determined qualitatively, in vitro, and represented as agrading system based on the ability of the SERMs to inhibit growth. Thenumber −4 is for compounds that induced 100% growth inhibition at 1 uM,−3 for compounds that inhibit growth by about 75-90%, −2 for about50-70% and −1 for inhibition less than 50% growth.

Toremifene and compounds 4a, 3l, 4e, 4u, 4b, 4r and 4h each inhibitedgrowth (data not shown). Toremifene inhibited growth to a level of −2,as did compounds 3l, and 4h. Compounds 4a, 4e and 4b showed moderateinhibition (−1); 4u and 4r demonstrated appreciably greater inhibitionrepresented qualitatively as −3 and −4, respectively.

Example 6 In Vivo Estrogenic Activity of Some Embodiments of theCompounds Materials and Methods

Female rats were administered increasing doses of toremifene, estrogenand the respective SERMs, and/or ICI-182,780 and uterine weights weredetermined Rats that were administered the vehicle alone served ascontrols.

Results

Rats given compounds 4a, 3d and 4g exhibited estrogenic activity, interms of increased uterine weight, under the conditions tested (FIGS. 12& 13). When 4a, 4g were coadministered with estrogen, an increase inuterine weight was observed. ICI-182,780 reversed 4a and 4g effects onuterine weight increase under these conditions.

Compounds 3e, 3l, 4h and 4e exhibited no estrogenic, or anti-estrogenicactivity in uterus, and compounds 3a, 3f, 4g, and 4a exhibitedestrogenic activity, in vivo (data not shown).

Example 7 Metabolic Stability of Some Embodiments of the Compounds inHuman Liver Microsomes Materials and Methods

Human liver microsomes were utilized as a representative system in orderto assess the potential of the compounds to form pharmacologicallyinactive or undesired potentially toxic metabolites due to phase Imetabolism.

Each substrate or reference control was dissolved at a concentration of10 mM in DMSO, from which a 5 μM spiking solution was prepared bydilution in water. Substrates (1 μM) were incubated in the presence ofhuman liver microsomes (Xenotech LLC, Kansas City Mo.) at 0.5 mg/mLfortified with an NADPH regenerating system at 37° C. and pH 7.4. TheNADPH regenerating system consisted of glucose-6-phosphate dehydrogenase(1 units/mL) in 0.05M K₂HPO₄. Duplicate incubations were performed in96-well polypropylene cluster tubes in a final volume of 250 μL perreaction. At 0, 2, 4, 6, 10, 30, and 60 minutes a stop solution (300 μLacetonitrile) was added to aliquots of the reaction mixture.Precipitated protein was removed by centrifugation (3000 rpm for 15minutes) and the supernatants were transferred to clean 96-well platesfor analysis.

LC-MS/MS Analysis:

The samples were injected onto a Phenomenex Luna hexylphenyl 50×2 mmi.d. 5 uM, column fitted with a guard column. An isocratic mobile phaseconsisting of 50% acetonitrile and 0.1% formic acid in water was used ata flow rate of 0.3 mL/min. The protonated molecular ion (M+H)⁺ of theanalyte was monitored by MDS/Sciex API 4000QTrap triple quadrupole massspectrometer using electrospray positive mode ionization with atemperature of 500° C. and a spray voltage of 4000V. Total analysis timewas 1.5 min per sample.

Data Evaluation:

Metabolic stability was defined as the amount of substrate metabolizedby the incubation with hepatic microsomes and expressed as a percentageof the initial amount of substrate (% remaining) based on peak area.Initial substrate concentration for each analyte was 1 μM. The initialpeak area of each substrate was determined at time zero and metabolicstability was assessed based on the change in analyte peak area fromtime 0 min to a single fixed timepoint for each sample (2-60 min,representative timepoints are shown in Table 2 below).

Results

Table 2. shows the percent of substrate remaining after designatedincubation intervals (0-60 minutes)

TABLE 2 % Remaining Substrate 0 min 10 min 30 min 60 min ^(a)Propranolol100 76 69 56 ^(b)Verapamil 100 101 36 11 3a 100 140 118 103 4a 100 10595 74 3k 100 119 120 94 4h 100 99 86 70 ^(a)Human Liver Microsomes SlowReference Control ^(b)Human Liver Microsomes Intermediate ReferenceControl

Four embodiments of the compounds tested showed reasonable stability inthe Phase I metabolic system compared to verapamil, a known substratefor cytochrome P450-mediated inactivation in human liver microsomes (SeeTable 2). Compounds 3a and 3k were resistant to oxidative and reductivereactions, with 103 and 94% of the initial substrate remaining,respectively, after a 60 minute reaction time. 4a and 4h showed moderatereactivity in the assay, with 74 and 70% remaining after the incubationperiod. These data suggest that the piperidine ring substitution on the4a and 4h compounds render them partially susceptible to Phase Imetabolic transformation. Generally the compounds evaluated are notlikely to have significant Phase I-mediated first pass hepaticextraction. As the determination of metabolic stability is but an invitro measure to describe the rate and extent of the potential in vivometabolic fate of the compounds, additional studies are ongoing toidentify other metabolic pathways which likely contribute to thebiologic inactivation of the leads, elucidate the structure of relevantmetabolites, and confirm whether the in vivo pharmacokinetic profile isconsistent with these preliminary in vitro data.

Example 8 General Synthesis of N,N-bis Aryl Benzamide Derivatives

General synthesis of diarylanilines. A mixture of arylamine (1.5equivalent), aryl iodide (1 equivalent), K₂CO₃ (2 equivalents), CuI (0.1equivalent) and L-proline (0.2 equivalent) were mixed together anddissolved in anhydrous DMSO at room temperature. Then, the reactionmixture was stirred and heated to 90° C. for 28 hours. The mixture wascooled to room temperature and hydrolyzed with water. EtOAc was added topartition the solution. The EtOAc layer was separated, washed withbrine, dried over anhydrous MgSO₄. The solvent was removed under reducedpressure. The solid residue was purified by flash column chromatography(silica gel) using 5% EtOAc/hexanes as eluent to afford thecorresponding diarylaniline.

Bis-(4-methoxyphenyl)amine (1a): pale-yellow solid, 73% yield. M.p.98.6-99.0° C. ¹H NMR (CDCl₃, 300 MHz) δ 6.93-6.81 (m, 8H), 5.37 (s, br,1H), 3.78 (s, 6H). MS m/z 228.4 (M−H)⁺.

N-(4-Methoxyphenyl)-phenylamine (1b): pale-yellow solid, 70% yield. M.p.106.3-106.5° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.24-7.18 (m, 3H), 7.08-7.06(m, 2H), 6.92-6.84 (m, 4H), 5.61 (s, br, 1H), 3.79 (s, 3H). MS m/z 200.1(M+H)⁺.

N-(4-Methoxyphenyl)-N-3-methoxyphenylamine (1c): pale-yellow solid, 54%yield. M.p. 69.7-70.0° C. ¹H NMR (CDCl₃, 300 MHz) δ 6.93-6.81 (m, 8H),5.37 (s, br, 1H), 3.78 (s, 6H). MS m/z 228.4 (M−H)⁺.

N-(4-Fluorophenyl)-N4-methoxyphenylamine (1d): pale-yellow solid, 54%yield. M.p. 60.6-61.0° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.01-6.83 (m, 8H),3.78 (s, 3H). MS m/z 217 (M)⁺.

N-(4-Methoxyphenyl)-N-1-naphthylamine (1e): pale-yellow solid, 54%yield. M.p. 105.8-106.0° C. ¹H NMR (CDCl₃, 500 MHz) δ 8.00 (d, 1H, J=8.0Hz), 7.92 (d, 1H, J=8.0 Hz), 7.50-7.43 (m, 3H), 7.33-7.30 (m, 1H), 7.10(d, 1H, J=7.5 Hz), 7.05 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.5 HZ), 3.80(s, 3H). MS m/z 249 (M)⁺.

N-(4-Benzyloxyphenyl)-N4-methoxyphenylamine (1f): pale-yellow solid, 54%yield. M.p. 108.0-108.4° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.34-7.08 (m, 5H),6.90-6.81 (s, 3H), 3.78 (s, 3H). MS m/z 306 (M+H)⁺.

N-[4-(Benzyloxy)phenyl]biphenyl-4-amine (1g): tan solid, 40.2% yield.M.p. 136-138° C. ¹H NMR (CDCl₃, 300 MHz) δ 5.04 (s, 2H, CH₂), 6.93-6.99(m, 4H, ArH), 7.02-7.11 (m, 2H, ArH), 7.22-7.48 (m, 9H, ArH), 7.53-7.56(m, 3H, ArH). MS m/z 352.2 (M+H)⁺.

N-[4-(Benzyloxy)phenyl]biphenyl-4-amine (1h): tan solid. 40.2% yield.M.p. 136-138° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.56-7.53 (m, 3H, ArH),7.48-7.22 (m, 9H, ArH), 7.11-7.02 (m, 2H, ArH), 6.99-6.93 (m, 4H, ArH),5.04 (s, 2H, CH₂); MS m/z 352.2 (M+H)⁺.

Example 9 General Synthesis of Benzamides

A mixture of arylaniline (1 equivalent), benzoyl chlorides (1.3equivalents), and pyridine (6 equivalents) was mixed together anddissolved in anhydrous THF at room temperature. The mixture was stirredand refluxed for 24 hours. The reaction solution was cooled to roomtemperature, and hydrolyzed by addition of 2N HCl solution. The solutionwas extracted with ethyl acetate. The organic layer was washed with asaturated aqueous NaHCO₃ solution to remove excess acid, dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography using EtOAc/hexanes(3/7 v/v) to afford the corresponding benzamide compounds.

4-Methoxy-N,N-bis-(4-methoxyphenyl)-benzamide (2a): white solid, 98%yield. M.p. 119.5-120° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.42 (d, 2H, J=8.9Hz), 7.05 (d, 4H, J=8.8 Hz), 6.81 (d, 4H, J=8.9 Hz), 6.71 (d, 2H, J=8.9Hz), 3.77 (s, 9H). MS m/z 364 (M+H).

3-Methoxy-N,N-bis-(4-methoxyphenyl)-benzamide (2b): white solid, 99%yield. M.p. 113.5-113.6° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.17-7.14 (m,5H), 6.97-6.95 (m, 3H), 6.87-6.84 (m, 4H). MS m/z 364 (M+H)⁺.

4-Methoxy-N-(4-methoxyphenyl)-N-(3-methoxyphenyl)-benzamide (2c): whitesolid, 79% yield. M.p. 154.5-154.9° C. ¹H NMR (CDCl₃, 300 MHz) δ7.47-7.43 (m, 2H), 7.31-7.13 (m, 7H), 6.75-6.68 (m, 4H), 3.77 (s, 3H),3.71 (s, 3H). MS m/z 356 (M+Na)⁺.

N,N-Bis-(4-methoxyphenyl)-benzamide (2d): white solid, 98% yield. M.p.77-77.5° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.46-7.42 (m, 2H), 7.29-7.17 (m,3H), 7.09-7.06 (m, 4H), 6.81-6.78 (m, 4H), 3.76 (s, 6H). MS m/z 356(M+Na)⁺.

4-Methoxy-N,N-diphenyl-benzamide (2e): white solid, 99% yield. M.p.133.5-133.9° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.45-7.42 (m, 2H), 7.29-7.24(m, 4H), 7.18-7.12 (m, 6H), 6.71-6.68 (m, 2H), 3.74 (s, 3H). MS m/z 326(M+Na)⁺.

3-Methoxy-N,N-diphenyl-benzamide (2f): white solid, 98% yield. M.p.122-122.2° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.45-7.42 (m, 2H), 7.29-7.24 (m,4H), 7.18-7.12 (m, 6H), 6.71-6.68 (m, 2H), 3.74 (s, 3H). MS m/z 326(M+Na)⁺.

N,N-Diphenyl-benzamide (2g): white solid, 89% yield. M.p. 178.4-179.3°C. ¹H NMR (CDCl₃, 300 MHz) δ 7.46-7.44 (m, 2H), 7.28-7.23 (m, 5H),7.21-7.14 (m, 8H). MS m/z 296 (M+Na)⁺.

N-(4-Methoxyphenyl)-N-phenyl-benzamide (2h): white solid, 95% yield.M.p. 153-154.2° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.47-7.43 (m, 2H),7.30-7.02 (m, 8H), 6.83-6.78 (m, 2H), 3.76 (s, 3H). MS m/z 326 (M+Na)⁺.

N-(3-Methoxyphenyl)-N-phenyl-benzamide (2i): white solid, 93% yield.M.p. 103-105.9° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.49-7.45 (m, 2H),7.31-7.15 (m, 9H), 6.75-6.70 (m, 3H), 3.76 (s, 3H). MS m/z 326 (M+Na)⁺.

4-Methoxy-N-(4-methoxyphenyl)-N-phenyl-benzamide (2j): white solid, 78%yield. ¹H NMR (CDCl₃, 300 MHz) δ 7.44-7.41 (m, 2H), 7.28-7.26 (m, 2H),7.15-7.05 (m, 5H), 6.83-6.80 (m, 2H), 6.72-6.70 (m, 2H), 3.77 (s, 6H).MS m/z 356 (M+Na)⁺.

4-Methoxy-N-(3-methoxyphenyl)-N-phenyl-benzamide (2k): white solid, 84%yield. M.p. 119.0-119.5° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.47-7.43 (m, 2H),7.31-7.13 (m, 7H), 6.75-6.68 (m, 4H), 3.77 (s, 3H), 3.71 (s, 3H). MS m/z356 (M+Na)⁺.

N,N-Bis(4-methoxyphenyl)-4-fluorobenzamide (2l): white solid, 98% yield.M.p. 122.2-122.4° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.46-7.42 (m, 2H),7.29-7.17 (m, 3H), 7.09-7.06 (m, 4H), 6.81-6.78 (m, 4H), 3.76 (s, 6H).MS m/z 356 (M+Na)⁺.

4-Methoxy-N,N-diphenyl-sulfonamide (2m): white solid, 89% yield. M.p.153.0-153.5° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.64-7.61 (m, 2H), 7.34-7.22(m, 10H), 6.94-6.91 (m, 2H), 3.86 (s, 3H). MS m/z 362 (M+Na)⁺.

4-Methoxy-N-(4-methoxyphenyl)-N-(4-fluorophenyl)-benzamide (2n): whitesolid, 97% yield. M.p. 133.5.0-134.5° C. ¹H NMR (CDCl₃, 300 MHz) δ8.11-6.66 (m, 15H), 3.74 (s, 3H), 3.73 (s, 3H). MS m/z 384 (M+H)⁺.

4-Methoxy-N-(4-methoxyphenyl)-N-(1-naphthyl)-benzamide (2o): whitesolid, 65% yield. M.p. 144.0-144.5° C. ¹H NMR (CDCl₃, 300 MHz) δ8.11-6.66 (m, 15H), 3.74 (s, 3H), 3.73 (s, 3H). MS m/z 384 (M+H)⁺.

N-(4-Methoxyphenyl)-N-(4-benzyloxyphenyl)-1-naphthylamide (2p). whitesolid, 95% yield. M.p. 143.5-144.0° C. ¹H NMR (CDCl₃, 300 MHz) δ8.25-8.22 (m, 1H), 7.79-7.69 (m, 2H), 7.57-7.22 (m, 9H), 6.96-6.63 (m,8H), 4.99 (s, 2H), 3.71 (s, 3H). MS m/z 460 (M+H)⁺.

4-Chloro-N-(4-methoxyphenyl)-N-(4-benzyloxyphenyl)-benzamide (2q): whitesolid, 96% yield. M.p. 130.0-131.4° C. ¹H NMR (DMSO-d₆, 300 MHz) δ. MSm/z 444 (M+H)⁺.

4-Cyano-N-(4-methoxyphenyl)-N-(4-benzyloxyphenyl)-benzamide (2r): whitesolid, 85% yield. M.p. 147.6-148.0° C. ¹H NMR (DMSO-d₆, 300 MHz) δ. MSm/z 435 (M+H)⁺.

N-(4-Methoxyphenyl)-N-(4-benzyloxyphenyl)-2-naphthylamide (2s): whitesolid, 58% yield. M.p. 174.9-175.5° C. ¹H NMR (CDCl₃, 300 MHz) δ 8.04(s, 1H), 7.77-7.74 (m, 2H), 7.64-7.61 (m, 1H), 7.51-7.43 (m, 4H),7.40-7.31 (m, 4H), 7.13-7.10 m, 4H), 6.88-6.78 (m, 4H), 4.99 (s, 2H),3.74 (s, 3H). MS m/z 460 (M+H)⁺.

4-(Benzyloxy)-N-[4-(benzyloxy)phenyl]-N-(4-methoxyphenyl)benzamide (2t):tan solid. 72.4% yield. M.p. 175-178° C. ¹H NMR (DMSO-d₆, 300 MHz) δ7.37-7.34 (m, 12H, ArH), 7.13-7.10 (m, 4H, ArH), 6.96-6.89 (m, 2H, ArH),6.88-6.86 (m, 4H, ArH), 5.06 (s, 4H, 2×CH₂), 3.72 (s, 3H, OCH₃). MS m/z516.3 (M+H)⁺.

N-[4-(Benzyloxy)phenyl]-4-methoxy-N-(4-methoxyphenyl)benzamide (2u):yellow oil. 71.3% yield. ¹H NMR (CDCl₃, 300 MHz) δ 7.44-7.34 (m, 7H,ArH), 7.07-7.04 (m, 4H, ArH), 6.89-6.86 (m, 2H, ArH), 6.82-6.79 (m, 2H,ArH), 6.72-6.69 (m, 2H, ArH), 5.01 (s, 2H, CH₂), 3.77 (s, 6H, 2 X OCH₃).MS m/z 462.1 (M+Na)⁺.

N-[4-(Benzyloxy)phenyl]-N-biphenyl-4-yl-4-methoxybenzamide (2v):light-yellow foam. 78.6% yield. M.p. 70-72° C. ¹H NMR (DMSO-d₆, 300 MHz)δ 7.66-7.57 (m, 4H, ArH), 7.47-7.32 (m, 10H, ArH), 7.30-7.23 (m, 2H,ArH), 7.18-7.07 (m, 2H, ArH), 7.00-6.92 (m, 2H, ArH), 6.89-6.80 (m, 2H,ArH), 5.06 (s, 2H, CH₂), 3.72 (s, 3H, OCH₃). MS m/z 508.3 (M+Na)⁺.

4-Cyano-N-(4-methoxyphenyl)-N-phenylbenzamide (2w): pale-yellow solid.96.3% yield. M.p. 125-128° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.77-7.74 (m,2H, ArH), 7.61-7.58 (m, 2H, ArH), 7.34-7.21 (m, 7H, ArH), 6.88 (d,J=7.92 Hz, 2H, ArH), 3.71 (s, 3H, OCH₃). MS m/z 351.1 (M+Na)⁺.

3-Methoxy-N-(4-methoxyphenyl)-N-phenylbenzamide (2x): pale-yellow oil.98.8% yield. ¹H NMR (CDCl₃, 300 MHz) δ 7.30-7.25 (m, 2H, ArH), 7.18-7.07(m, 6H, ArH), 7.01-6.98 (m, 2H, ArH), 6.83-6.80 (m, 3H, ArH), 3.77 (s,3H, OCH₃), 3.68 (s, 3H, OCH₃). MS m/z 356.1 (M+Na)⁺.

4-Cyano-N-(3-methoxyphenyl)-N-phenylbenzamide (2y): brown oil. 84.8%yield. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.77-7.75 (m, 2H, ArH). 7.63-7.61 (m,2H, ArH), 7.35-7.30 (m, 4H, ArH), 7.25-7.22 (m, 2H, ArH), 6.91 (s, 1H,ArH), 6.83-6.80 (m, 2H, ArH), 3.67 (s, 3H, OCH₃). MS m/z 351.1 (M+Na)⁺.

4-Cyano-N,N-diphenylbenzamide (2z): tan solid. 85.2% yield. M.p.145-147° C. ¹H NMR (DMSO-d₆, 300 MHz) δ7.76-7.74 (m, 2H, ArH), 7.61-7.59(m, 2H, ArH), 7.34-7.22 (m, 10H, ArH). MS m/z 321.0 (M+Na)⁺.

Example 10 General Procedure for Demethylation of Benzamide DerivativesUsing BBr₃

A methoxybenzamide compound was dissolved in dry CH₂Cl₂. BBr₃ (1.0 MCH₂Cl₂ solution) was added dropwise at 0° C. The reaction solution wasslowly warmed to room temperature and allowed to stir overnight at roomtemperature. The mixture was cooled to 0° C. in an ice bath andhydrolyzed by adding water. EtOAc was added to partition the solution.The organic layer was separated; the aqueous layer was extracted withEtOAc. The organic layer was washed with brine and dried over anhydrousMgSO₄. The solvent was removed under reduced pressure. The residue waspurified by flash column chromatography using CH₃OH/CH₂Cl₂ (1/9 v/v) toafford the phenolic compounds.

The following compounds where synthesized as described herein above andcharacterized and summarized in Table 1:4-Hydroxy-N,N-bis-(4-hydroxyphenyl)-benzamide (3a);3-Hydroxy-N-bis-(4-hydroxyphenyl)-benzamide (3b);4-Hydroxy-N-(4-hydroxyphenyl)-N-(3-hydroxyphenyl)-benzamide (3c);N,N-Bis-(4-hydroxyphenyl)-benzamide (3d);4-Hydroxy-N,N-diphenyl-benzamide (3e); 3-Hydroxy-N,N-diphenyl-benzamide(3f); N-(4-Hydroxyphenyl)-N-phenyl-benzamide (3g);N-(3-Hydroxyphenyl)-N-phenyl-benzamide (3h);4-Hydroxy-N-(4-hydroxyphenyl)-N-phenyl-benzamide (3i);4-Hydroxy-N-(3-hydroxyphenyl)-N-phenyl-benzamide (3j);N,N-Bis(4-hydroxyphenyl)-4-fluorobenzamide (3k);4-Hydroxy-N,N-diphenyl-phenylsulfonamide (3l);4-Hydroxy-N-(4-hydroxyphenyl)-N-(4-fluorophenyl)-benzamide (3m);N,N-Bis(4-hydroxyphenyl)-1-naphthylamide (3n);4-Hydroxy-N-(1-Naphthyl)-N-(4-hydroxyphenyl)-benzamide (3o);4-Cyano-N,N-Bis(4-hydroxyphenyl)-benzamide (3p);3-Cyano-N,N-Bis(4-hydroxyphenyl)-benzamide (3q);N,N-Bis(4-hydroxyphenyl)-2-naphthylamide (3r);4-Cyano-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-hydroxyphenyl)-benzamide(3s);3-Chloro-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-hydroxyphenyl)-benzamide(3t); N-Biphenyl-4-yl-N-(4-hydroxyphenyl)-4-methoxybenzamide (3u);N-Biphenyl-4-yl-4-hydroxy-N-(4-hydroxyphenyl)-benzamide (3v);4-Hydroxy-N-(4-hydroxyphenyl)-N-[4-(2-piperidin-1-ylethoxy)phenyl]-benzamide(3w); 3-Hydroxy-N-(4-hydroxyphenyl)-N-phenyl-benzamide (3x);N-Biphenyl-4-yl-4-hydroxy-N-[4-(2-piperidin-1-ylethoxy)phenyl]-benzamide(3y); 4-Cyano-N-(4-hydroxyphenyl)-N-phenylbenzamide (10a);N,N-bis(4-hydroxyphenyl)biphenyl-4-carboxamide (10c),N,N-bis(4-hydroxyphenyl)-3,4-dimethylbenzamide (10d);N-(biphenyl-4-yl)-4-cyano-N-(4-hydroxyphenyl)-benzamide (10e);3-fluoro-4-hydroxy-N-(4-hydroxyphenyl)-N-phenylbenzamide (10f);4-hydroxy-N,N-bis(4-hydroxyphenyl)-3,5-dimethylbenzamide (10i);N,N-bis(4-hydroxyphenyl)-2,3-dimethylbenzamide (10j);3-fluoro-4-hydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (10k);N,N-bis(4-hydroxyphenyl)-4-propylbenzamide (10l);3,4-dihydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (10m);4-hydroxy-N,N-bis(4-hydroxyphenyl)-3-methylbenzamide (10n);N,N-bis(4-hydroxyphenyl)-2,4-dimethylbenzamide (10q);N,N-bis(4-hydroxyphenyl)-4-methylbenzamide (10s);4,4′-(2,3-dimethylbenzylazanediyl)diphenol (10t);4-formyl-N,N-bis(4-hydroxyphenyl)-benzamide (10u);N,N-bis(4-hydroxyphenyl)-4-(trifluoromethyl)benzamide (11b);N,N-bis(4-hydroxyphenyl)-4-nitrobenzamide (11d);3-fluoro-N,N-bis(4-hydroxyphenyl)benzamide (11e);N,N-bis(4-hydroxyphenyl)-4-methoxy-1-naphthamide (11i);4-((hydroxyimino)methyl)-N,N-bis(4-hydroxyphenyl)benzamide (11l);N,N-bis(4-hydroxyphenyl)-4-pentylbenzamide (11p);4-tert-butyl-N,N-bis(4-hydroxyphenyl)benzamide (11r);3-{4-[Bis-(4-hydroxy-phenyl)-carbamoyl]-phenyl}-acrylic acid (11t);3-{4-[Bis-(4-hydroxy-phenyl)-carbamoyl]-phenyl}-propionic acid (11u);N,N-Bis-(4-hydroxy-phenyl)-4-(3-hydroxy-propyl)-benzamide (11v);N-(4-hydroxyphenyl)-4-(3-hydroxypropyl)-N-(4-methoxyphenyl)-benzamide(11w); 4-fluoro-N,N-bis(4-hydroxyphenyl)-2-(trifluoromethyl)-benzamide(11x);3-fluoro-N-(4-fluorophenyl)-4-hydroxy-N-(4-hydroxyphenyl)benzamide(11y); and N,N-bis(4-hydroxyphenyl)-isonicotin-amide (11aa).

General Procedures for Debenzylation of Benzyloxyphenyl-Benzamides.

Compound was dissolved in EtOH in a 250 mL hydrogenation bottle. Pd/Cpowder (5% mol) was added to the solution. The reaction vessel wasmounted to a hydrogenation apparatus under 20 psi pressure hydrogen gas.The reaction was monitored by TLC until the disappearance of startingmaterial. Then, the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography withhexanes/EtOAc=3/2 v/v to afford the desired product.

The following compounds where synthesized as described herein above andcharacterized and summarized in Table 1:4-Chloro-N-[4-hydroxyphenyl]-N-(4-methoxyphenyl)-benzamide (5a);4-Cyano-N-[4-hydroxyphenyl]-N-(4-methoxyphenyl)-benzamide (5b);3-Chloro-N-[4-hydroxyphenyl]-N-(4-methoxyphenyl)-benzamide (5c);4-Hydroxy-N-(4-hydroxyphenyl)-N-(4-methoxyphenyl)-benzamide (5d);N-(4-Hydroxyphenyl)-4-methoxy-N-(4-methoxyphenyl)-benzamide (5e).

Example 11 General Synthesis of O-(2-piperidin-1-ylethoxy)-Benzamidesand Analogues

To a solution of hydroxyphenyl containing benzamide analogue (1equivalent) in acetone, K₂CO₃ (3 equivalents) andN-chloroethyl-piperidine hydrochloride salt (1.2 equivalents) wereadded. The solution was heated to reflux for 6 hours. The solution wasevaporated to dryness. The residue was hydrolyzed by adding water, andthen extracted with ethyl acetate. The organic layers were separated anddried over anhydrous MgSO₄. The solvent was removed under reducedpressure. The residue was purified by flash chromatography withmethylene chloride/methanol=9/1 v/v to give the desired compound. Thehydrochloride salts were prepared by adding HCl in Et₂O to the methanolsolution of the compounds followed by evaporation of solvents.

The following compounds where synthesized as described herein above andcharacterized and summarized in Table 1:N-(4-Hydroxyphenyl)-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-benzamide(4a); N-(phenyl)-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-benzamide (4b);N,N-diphenyl-[3-(2-piperidinylethoxy)]-benzamide hydrochloride (4c);N,N-diphenyl-[3-(2-piperidinylethoxy)]-benzamide hydrochloride (4d);N-(4-Hydroxyphenyl)-N-phenyl-[4-(2-piperidin-1-ylethoxy)]-benzamidehydrochloride (4e);N,N-diphenyl-bis[4-(2-piperidin-1-ylethoxy)-phenyl]-sulfonamidehydrochloride (4f);N-(4-Fluorophenyl)-N-[4-hydroxyphenyl]-[4-(2-piperidin-1-ylethoxy)]-benzamide(4g);N-(4-Hydroxyphenyl)-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-4-fluoro-benzamidehydrochloride (4h);3-(2-piperidin-1-ylethoxy)-N,N-bis(4-hydroxyphenyl)-benzamide (4i);4-Cyano-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-methoxyphenyl)-benzamide(4j);4-Chloro-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-methoxyphenyl)-benzamide(4k);4-Cyano-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-methoxyphenyl)-benzamide(4l);3-Chloro-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-(4-methoxyphenyl)-benzamide(4m);4-Methoxy-N-(4-methoxyphenyl)-N-[4-(2-piperidin-1-ylethoxy)phenyl]-benzamide(4n);N-Biphenyl-4-yl-N-(4-hydroxyphenyl)-4-(2-piperidin-1-ylethoxy)-benzamide(4o); 4-Methoxy-N-phenyl-N-[4-(2-piperidin-1-ylethoxy)phenyl]-benzamide(4p); N-(4-Hydroxyphenyl)-N-phenyl-3-(2-piperidin-1-ylethoxy)-benzamide(4q);N-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-4-propylbenzamide(10o);N-(4-hydroxyphenyl)-2,3-dimethyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-benzamide (10p);N-(4-hydroxyphenyl)-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)benzamide(11a);N-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-4-(trifluoromethyl)benzamide (11c);N-(4-Hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1-naphthamide(11f);3-fluoro-N-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11g);N-(4-hydroxyphenyl)-4-nitro-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11h);N-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2-naphthamide(11j);N-(4-hydroxyphenyl)-2,4-dimethyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11m);N-(4-hydroxyphenyl)-3,5-dimethyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11n);4-((2,3-dimethylbenzyl)(4-(2-(piperidin-1-yl)ethoxy)phenyl)amino)phenol(11o);N-(4-hydroxyphenyl)-4-pentyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11q);4-tert-butyl-N-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11s);N-(4-hydroxyphenyl)-4-methyl-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)benzamide(11z); andN-(4-hydroxyphenyl)-N-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-isonicotinamide(11ab).

Synthesis of Two-Tailed SERMs

N-(4-Fluorophenyl)-N-[4-(2-piperidin-1-ylethoxy)-phenyl]-[4-(2-piperidin-1-yl-ethoxy)]-benzamidedihydrochloride (4r);N,N-Bis[4-(2-piperidin-1-ylethoxy)-phenyl]-4-fluoro-benzamidedihydrochloride (4s);N,N-Bis[4-(2-piperidin-1-ylethoxy)-phenyl]-benzamide dihydrochloride(4t); andN-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-phenyl-[4-(2-piperidin-1-ylethoxy)]-benzamide dihydrochloride (4u).

Example 12 General Procedures for Synthesis of CyclohexanecarboxylicAcid Bis-Arylamides

N-Cyclohexyl-4-methoxyphenylamine. This compound was synthesizedaccording the literature. The NMR, MS data and melting point areconsistent with those reported in literature.^(ref) (D. Ma, Q. Cai, H.Zhang, Org. Lett. 2003, 5, 2453.)

General Procedures for Synthesis of Cyclohexanecarboxylic Acid Bis-ArylAmides.

Arylaniline (1 equivalent), cyclohexylcarbonyl chloride (1.3equivalents), and pyridine (6 equivalents). The reaction mixture wasstirred and heated to 90° C. for 24 hours. The reaction solution wascooled to room temperature, and hydrolyzed by addition of 2N HClsolution. The solution was extracted with ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous NaHCO₃solution to remove excess acid, dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography using EtOAc/hexanes (3/7 v/v) to afford thecorresponding cyclohexylamide compound.

Cyclohexanecarboxylic acidN-(4-methoxyphenyl)-N-(4-benzyloxyphenyl)-amide (8a): white solid, 92%yield. M.p. 102.7-128.0° C. ¹H NMR (CDCl₃, 300 MHz) δ 7.40-6.90 (m,13H), 5.03 (s, 2H), 3.80 (s, 3H), 2.41-2.04 (m, 1H), 1.78-1.53 (m, 7H),1.28-1.06 (m, 3H). MS m/z 438 (M+Na)⁺.

General Procedure for Synthesis of Bis N-HydroxyphenylCyclohexanecarboxylic Acids.

A methoxyphenylcyclohexylamide compound was dissolved in dry CH₂Cl₂.BBr₃ (1.0 M CH₂Cl₂ solution) was added dropwise with stirring via asyringe at 0° C. The reaction solution was slowly warmed to roomtemperature and allowed to stir overnight at room temperature. Themixture was cooled to 0° C. in an ice bath and hydrolyzed by addingwater. EtOAc was added to partition the solution. The organic layer wasseparated; the aqueous layer was extracted with EtOAc twice. The organiclayers were combined, washed with brine and dried over anhydrous MgSO₄.The solvent was removed under vacuum. The residue was purified by flashcolumn chromatography using silica-gel with CH₃OH/CH₂Cl₂ (1/9 v/v) toafford the pure desired phenolic compound.

Cyclohexanecarboxylic acid bis(4-hydroxyphenyl)-amide (8b): white solid,86% yield. M.p. 265.1-266.2° C. (decomposed). ¹H NMR (DMSO-d₆, 500 MHz)δ 9.65 (s, 1H), 9.37 (s, 1H), 7.17-6.70 (m, 4H), 6.78-6.67 (m, 4H),2.29-2.23 (m, 1H), 1.71-1.62 (m, 4H), 1.54-1.51 (m, 1H), 1.41-1.32 (m,2H), 1.21-1.07 (m, 1H), 0.97-0.90 (m, 2H). MS m/z 334 (M+Na)⁺.

Example 13 General Synthesis of5-[4-methoxyphenyl]-5H-phenanthridin-6-ones

A mixture of 6-(5H)-phenathridinone (1.5 equivalent), 4-iodoanisole (1equivalent), K₂CO₃ (2 equivalents), CuI (0.1 equivalent) and L-proline(0.2 equivalent) were mixed together and dissolved in anhydrous DMSO atroom temperature. Then, the reaction mixture was stirred and heated to150° C. for 28 hours. The mixture was cooled to room temperature andhydrolyzed with water. EtOAc was added to partition the solution. TheEtOAc layer was separated, washed with brine, dried over anhydrousMgSO₄. The solvent was removed under reduced pressure. The residue waspurified by flash column chromatography (silica gel) using EtOAc/hexanes(2/3 v/v) to afford the desired product.

5-[4-methoxyphenyl]-5H-phenanthridin-6-one (7a): yellow solid. 65%yield. M.p. 217.0-218.5° C. (decomposed). ¹H NMR (DMSO-d₆, 500 MHz) δ8.61-8.59 (m, 1H), 8.54-8.51 (m, 1H), 8.36-8.34 (m, 1H), 7.94-7.89 (m,1H), 7.71-7.66 (m, 1H), 7.43-7.28 (m, 4H), 7.19-7.16 (m, 2H), 6.63-6.60(m, 1H). MS m/z 302 (M+H)⁺.

General Synthesis of 5-[4-hydroxyphenyl]-5H-phenanthridin-6-ones

A 5-[4-methoxyphenyl]-5H-phenanthridin-6-one was dissolved in dryCH₂Cl₂. BBr₃ (1.0 M CH₂Cl₂ solution) was added dropwise with stirringvia a syringe at 0° C. The reaction solution was slowly warmed to roomtemperature and allowed to stir overnight at room temperature. Themixture was cooled to 0° C. in an ice bath and hydrolyzed by addingwater. EtOAc was added to partition the solution. The organic layer wasseparated; the aqueous layer was extracted with EtOAc twice. The organiclayers were combined, washed with brine and dried over anhydrous MgSO₄.The solvent was removed under vacuum. The residue was purified by flashcolumn chromatography using silica-gel with CH₃OH/CH₂Cl₂ (1/9 v/v) toafford the pure desired phenolic compound.

5-[4-hydroxyphenyl]-5H-phenanthridin-6-one (7b): yellow solid. 78%yield. M.p. 325.7-327.0° C. (decomposed). ¹H NMR (DMSO-d₆, 500 MHz) δ9.82 (s, 1H), 8.60-8.58 (m, 1H), 8.52-8.51 (m, 1H), 8.35-8.33 (m, 1H),7.92-7.89 (m, 1H), 7.69-7.66 (m, 1H), 7.41-7.38 (m, 1H), 7.32-7.29 (m,1H), 7.15-7.13 (m, 2H), 6.99-6.97 (m, 2H), 6.65-6.63 (m, 1H). MS m/z 310(M+Na)⁺.

General Synthesis of5-[4-(2-piperidin-1-ylethoxy)-phenyl]-phenanthridin-6-one Derivatives

To a solution of 5-[4-hydroxyphenyl]-phenanthridin-6-one (1 equivalent)in acetone, K₂CO₃ (3 equivalents) and N-chloroethylpiperidinehydrochloride salt (1.2 equivalents) were added. The solution was heatedto reflux for 6 hours. The solution was evaporated to dryness. Theresidue was hydrolyzed by adding water, and then extracted with ethylacetate. The organic layers were separated and dried over anhydrousMgSO₄. The solvent was removed under reduced pressure. The residue waspurified by flash chromatography (silica-gel; methylenechloride/methanol=9/1 v/v) to give the desired compound. Thehydrochloride salts were prepared by adding HCl in Et₂O to the methanolsolution of the compounds followed by evaporation of solvents.

5-[4-(2-piperidin-1-ylethoxy)-phenyl]-5H-phenanthridin-6-one (7c):yellow solid. 79% yield. M.p. 220.0-221.5° C. (decomposed). ¹H NMR(DMSO-d₆, 300 MHz) δ 8.56-8.53 (m, 1H), 8.35-8.29 (m, 2H), 7.84-7.79 (m,1H), 7.64-7.59 (m, 1H), 7.36-7.24 (m, 4H), 7.23-7.10 (m, 2H), 6.76-6.73(m, 1H), 4.45 (tr, 2H, J=5.1 Hz), 3.16 (tr, 2H, J=5.1 Hz), 2.94 (br,4H), 1.90-1.85 (m, 4H), 1.61-1.59 (m, 2H). MS m/z 399 (M+H)⁺.

Example 14 General Synthesis of 6b, 6c, 6d, 6e, 6f, and 6g

(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid. D-Proline, 14.93 g,0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath;the resulting alkaline solution was diluted with acetone (71 mL). Anacetone solution (71 mL) of metacryloyl chloride (13.56 g, 0.13 mol) and2N NaOH solution (71 mL) were simultaneously added over 40 min to theaqueous solution of D-proline in an ice bath. The pH of the mixture waskept at 10-11° C. during the addition of the metacryloyl chloride. Afterstiffing (3 h, room temperature), the mixture was evaporated in vacuo ata temperature at 35-45° C. to remove acetone. The resulting solution waswashed with ethyl ether and was acidified to pH 2 with concentrated HCl.The acidic mixture was saturated with NaCl and was extracted with EtOAc(100 mL×3). The combined extracts were dried over Na₂SO₄, filteredthrough Celite, and evaporated in vacuo to give the crude product as acolorless oil. Recrystallization of the oil from ethyl ether and hexanesafforded 16.2 (68%) of the desired compound as colorless crystals: mp102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of thiscompound demonstrated the existence of two rotamers of the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for thefirst rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2Hfor both rotamers, vinyl CH₂), 4.48-4.44 for the first rotamer,4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CHat the chiral canter), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH),1.97-1.72 (m, 6H, CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for majorrotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: forminor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7;IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369,1348, 1178 cm⁻¹; [α]_(D) ²⁶ +8.0° (c=1, MeOH); Anal. Calcd. forC₉H₁₃NO₃: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione.A solution of N-bromosuccimide (NBS) (23.5 g, 0.132 mol) in 100 mL ofDMF was added dropwise to a stirred solution of the(methyl-acryloyl)-pyrrolidine (16.1 g, 88 mmol) in 70 mL of DMF underargon at room temperature, and the resulting mixture was stirred 3 days.The solvent was removed in vacuo, and a yellow solid was precipitated.The solid was suspended in water, stirred overnight at room temperature,filtered, and dried to give 18.6 (81%) (smaller weight when dried ˜34%)of the title compound as a yellow solid: mp 152-154° C. (lit. [214] mp107-109° C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd,J=9.6 Hz, J=6.7 Hz, 1H, CH at the chiral center), 4.02 (d, J=11.4 Hz,1H, CHH_(a)), 3.86 (d, J=11.4 Hz, 1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂),2.30-2.20 (m, 1H, CH), 2.04-1.72 (m, 3H, CH₂ and CH), 1.56 (s, 2H, Me);¹³C NMR (75 MHz, DMSO-d₆) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0,22.9, 21.6; IR (KBr) 3474, 1745 (C═O), 1687 (C═O), 1448, 1377, 1360,1308, 1227, 1159, 1062 cm⁻¹; [α]_(D) ²⁶+124.5° (c=1.3, chloroform);Anal. Calcd. for C₉H₁₂BrNO₃: C, 41.24; H, 4.61; N, 5.34. Found: C,41.46; H, 4.64; N, 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid. A mixture of bromolactone(18.5 g, 71 mmol) in 300 mL of 24% HBr was heated at reflux for 1 h. Theresulting solution was diluted with brine (200 mL), and was extractedwith ethyl acetate (100 mL×4). The combined extracts were washed withsaturated NaHCO₃ (100 mL×4). The aqueous solution was acidified withconcentrated HCl to pH=1, which, in turn, was extracted with ethylacetate (100 mL×4). The combined organic solution was dried over Na₂SO₄,filtered through Celite, and evaporated in vacuo to dryness.Recrystallization from toluene afforded 10.2 g (86%) of the desiredcompound as colorless crystals: mp 107-109° C. (lit. [214] mp 109-113°C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz,1H, CHH_(a)), 3.52 (d, J=10.1 Hz, 1H, CHH_(b)), 1.35 (s, 3H, Me); IR(KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O), 1449, 1421, 1380, 1292,1193, 1085 cm⁻¹; [α]_(D) ²⁶ +10.5° (c=2.6, MeOH); Anal. Calcd. forC₄H₇BrO₃: C, 26.25; H, 3.86. Found: C, 26.28; H, 3.75.

Synthesis of(R)-3-bromo-2-hydroxy-N-(4-methoxyphenyl)-2-methylpropanamide (6b).(R)-3-Bromo-2-hydroxy-2-methylpropanic acid (8.54 g, 46.7 mmol) wasplaced in a 250 mL three-necked round-bottomed flask fitted with astirring bar and an addition funnel, and dissolved in 100 mL anhydrousTHF at room temperature. The solution was cooled to 0° C. Then, SOCl₂(7.78 g, 65.4 mmol) was added dropwise with stiffing in 3 hours.p-Anisidine (5.00 g, 40.6 mmol) and triethylamine (6.62 g, 65.4 mmol)were added to the mixture at 0° C. The reaction mixture was stirred atroom temperature overnight. The solvent was removed under reducedpressure to give a yellow residue which was dissolved in ethyl acetateand water. The organic layer was separated, washed with saturated NaHCO₃solution and dried over anhydrous MgSO₄. The solvent was removed andresidue was subjected to flash column chromatography (silica gel,EtOAc/hexanes=1/1 v/v) to give a white solid product, 8.50 g, 63.2%yield.

Synthesis of (S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide(6c). (R)-3-bromo-2-hydroxy-N-(4-methoxyphenyl)-2-methylpropanamide (6b)(5.80 g, 20.13 mmol) and K₂CO₃ (5.56 g, 40.26 mmol) were placed in a 500mL round-bottomed flask fitted with a stirring bar. 150 mL of acetonewas added at room temperature. The reaction solution was heated toreflux for 3 hours. The solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography (silica gel,EtOAc/hexanes=1/1 v/v) to give a white solid product,(S)—N-(4-methoxyphenyl)-2-methyloxirane-2-carboxamide, 4.00 g, 96.0%yield.

To a 500 mL single-necked round-bottomed flask fitted with a stirringbar, rubber stopper and a nitrogen inlet was added(S)—N-(4-methoxyphenyl)-2-methyloxirane-2-carboxamide (1.00 g, 4.83mmol) and anhydrous THF (50 mL). The solution was cooled to −78° C. indry ice-acetone bath. 4-Methoxyphenylmagnesium bromide solution (14.50mL of 0.5 M THF solution, 7.25 mmol) was added dropwise with stirring at−78° C. The resulted solution was stirred at −78° C. for 30 minutes andthen at room temperature for 3 hours. The reaction was quenched byadding 20 mL of saturated NH₄Cl solution at 0° C. EtOAc (3×30 mL) wasadded to extract the solution. The organic layers were separated, washedwith brine (20 mL) and dried over anhydrous MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by flashcolumn chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give awhite solid product,(S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide (6c), 0.60 g,39.5% yield.

Synthesis of(S)-2-hydroxy-3-(4-methoxyphenoxy)-N-(4-methoxyphenyl)-2-methylpropanamide(6d). (S)—N-(4-Methoxyphenyl)-2-methyloxirane-2-carboxamide (0.50 g,2.41 mmol), 4-methylphenol (0.39 g, 3.14 mmol) and K₂CO₃ (0.67 g, 4.82mmol) were placed in a 250 mL round-bottomed flask fitted with astirring bar. 100 mL of isopropanol was added at room temperature. Thereaction solution was heated to reflux for 3 hours. The solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography (silica gel, EtOAc/hexanes=2/3 v/v) to give a white solidproduct,(S)-2-hydroxy-3-(4-methoxyphenoxy)-N-(4-methoxyphenyl)-2-methylpropanamide(6d), 0.79 g, 98.8% yield.

Synthesis of(R)-3-bromo-2-hydroxy-N-(4-hydroxyphenyl)-2-methylpropanamide (6e).(R)-3-bromo-2-hydroxy-N-(4-methoxyphenyl)-2-methylpropanamide (6b) (0.55g, 1.91 mmol) was dissolved in 25 mL of anhydrous methylene chloride ina dry 250 mL round-bottomed flask fitted with a stirring bar, anitrogeninlet and rubber stopper. BBr₃ solution (16.0 mL of 0.5 M CH₂Cl₂solution, 8.0 mmol) was added dropwise with stirring at 0° C. Thereaction solution was stirred at room temperature overnight. Thereaction was quenched by adding 20 mL of water and extracted with EtOAc(3×30 mL). The EtOAc layers were separated and dried over anhydrousMgSO₄. The solvent was removed under reduced pressure. The residue waspurified by flash column chromatography (silica gel, EtOAc/hexanes=1/1v/v) to give a white solid product,(R)-3-bromo-2-hydroxy-N-(4-hydroxyphenyl)-2-methylpropanamide (6e), 0.51g, 97.9% yield.

Synthesis of(S)-2-hydroxy-3-(4-hydroxyphenoxy)-N-(4-hydroxyphenyl)-2-methylpropanamide(6f).(S)-2-hydroxy-3-(4-methoxyphenoxy)-N-(4-methoxyphenyl)-2-methylpropanamide(6d) (0.20 g, 0.60 mmol) was dissolved in dry CH₂Cl₂ (30 mL). BBr₃ (4 mLof 1.0 M CH₂Cl₂ solution) was added dropwise with stirring via a syringeat room temperature. The reaction solution was allowed to stir overnightat room temperature. The mixture was cooled to 0° C. in a ice bath andhydrolyzed by adding water (25 mL). EtOAc (50 mL) was added to partitionthe solution. The organic layer was separated; the aqueous layer wasextracted with EtOAc (2×10mL). The organic layers were combined, washedwith brine and dried over anhydrous MgSO₄. The solvent was removed undervacuum. The residue was purified by flash column chromatography usingsilica-gel with hexanes/EtOAc (3/7 v/v) to afford a white solid product,(S)-2-hydroxy-3-(4-hydroxyphenoxy)-N-(4-hydroxyphenyl)-2-methylpropanamide(6f), 0.13 g, 67.2% yield.

Synthesis of (S)-2-hydroxy-N,3-bis(4-hydroxyphenyl)-2-methylpropanamide(6g). (S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide (6c)(0.20 g, 0.63 mmol) was dissolved in dry CH₂Cl₂ (20 mL). BBr₃ (6 mL of1.0 M CH₂Cl₂ solution) was added dropwise with stirring via a syringe atroom temperature. The reaction solution was allowed to stir overnight atroom temperature. The mixture was cooled to 0° C. in a ice bath andhydrolyzed by adding water (25 mL). EtOAc (50 mL) was added to partitionthe solution. The organic layer was separated; the aqueous layer wasextracted with EtOAc (2×10 mL). The organic layers were combined, washedwith brine and dried over anhydrous MgSO₄. The solvent was removed undervacuum. The residue was purified by flash column chromatography usingsilica-gel with hexanes/EtOAc (3/7 v/v) to afford a white solid product,(S)-2-hydroxy-N,3-bis(4-hydroxyphenyl)-2-methylpropanamide (6g), 0.12 g,65.6% yield.

Example 15 Synthesis of 11k

Synthesis of 2-hydroxy-N,N,2-tri(4-hydroxyphenyl)propanamide (11k).Pyruvic acid (1.00 g, 11.34 mmol) was placed in a 250 mL three-neckedround-bottomed flask fitted with a stirring bar, reflux condenser and anitrogen inlet, and dissolved in 30 mL anhydrous THF at roomtemperature. Then, SOCl₂ (2.03 g, 17.01 mmol) was added dropwise withstirring in 3 hours at room temperature. Bis(4-methoxyphenyl)amine (2.00g, 8.72 mmol) was added under nitrogen protection. Pyridine (4.14 g,52.3 mmol) were added to the mixture at 0° C. The reaction mixture washeated to reflux for 12 hours. The reaction was quenched by adding 30 mLof 2N HCl solution. The mixture was extracted with EtOAc (3×20 mL). Theorganic layers were separated, washed with brine (20 mL) and dried overanhydrous MgSO₄. The solvent was removed under reduced pressure to givea yellow residue. The solvent was removed and residue was subjected toflash column chromatography (silica gel, EtOAc/hexanes=3/7 v/v) to givea white solid product, N,N-bis(4-methoxyphenyl)-2-oxopropanamide, 2.15g, 82.4% yield. MS: m/z 322 [M+Na]⁺.

N,N-bis(4-methoxyphenyl)-2-oxopropanamide (0.53 g, 1.77 mmol) was placedin a 250 mL three-necked round-bottomed flask fitted with a stiffingbar, a rubber stopper and a nitrogen inlet, and dissolved in 30 mLanhydrous THF. The solution was cooled to −78° C. in dry ice-acetonebath. 4-Methoxyphenylmagnesium bromide solution (3.89 mL of 0.5 M THFsolution, 7.25 mmol) was added dropwise with stiffing at −78° C. undernitrogen atmosphere. The resulted solution was stirred at −78° C. forone hour and then at room temperature for one hour. The reaction wasquenched by adding 20 mL of saturated NH₄Cl solution. EtOAc (3×30 mL)was added to extract the solution. The organic layers were separated,washed with brine (20 mL) and dried over anhydrous MgSO₄. The solventwas removed under reduced pressure and the residue was purified by flashcolumn chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give awhite solid product, 2-hydroxy-N,N,2-tris(4-methoxyphenyl)propanamide,0.61 g, 84.7% yield.

2-hydroxy-N,N,2-tris(4-methoxyphenyl)propanamide (0.60 g, 1.47 mmol) wasto dissolved in 30 mL of anhydrous methylene chloride in a dry 250 mLround-bottomed flask fitted with a stiffing bar, anitrogen inlet andrubber stopper. BBr₃ solution (6.00 mL of 1M CH₂Cl₂ solution, 6.00 mmol)was added dropwise with stiffing at 0° C. The reaction solution wasstirred at room temperature overnight. The reaction was quenched byadding 20 mL of water and extracted with EtOAc (3×30 mL). The EtOAclayers were separated and dried over anhydrous MgSO₄. The solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography (silica gel, CH₂Cl₂/MeOH=9/1 v/v) to give a white solidproduct, 2-hydroxy-N,N,2-tri(4-hydroxyphenyl)propanamide (11k), 0.42 g,77.8% yield.

Example 16 Toremifene Lowers Total LDL Cholesterol and Triglycerides andRaises HDL on Prostate Cancer Patients on Androgen Deprivation Therapy(ADT)

Methods:

1392 men 50 years old or more, with histologically documented prostatecancer and receiving ADT were randomized to toremifene (80 mg/day) orplacebo treated groups in a human clinical trial. An interim analysisevaluated changes in circulating lipid levels from baseline to month 12in the first 197 subjects to complete their first year to determinechanges in total cholesterol, low density lipoprotein (LDL) cholesterol,high density lipoprotein (HDL) cholesterol, triglycerides and the ratioof total circulating cholesterol to HDL levels in the respectivesubjects.

Results:

Prostate cancer patients having undergone Androgen Deprivation Therapy(ADT) who received toremifene were compared to placebo groups.Toremifene treatment resulted in lower total circulating cholesterol(−7.1%; p=0.001), LDL (−9.0%; p=0.003), and triglyceride (−20.1%;p=0.009) levels, a reduction in the total cholesterol/HDL ratio (−11.7%;p<0.001), and higher HDL levels (+5.4%; p=0.018) (FIG. 1).

Subjects concurrently administered Statins demonstrated furtherreduction of total cholesterol, yet the magnitude of lipid changeselicited by toremifene treatment was greater in patients who were notconcomitantly taking statins. Accordingly, patients treated withtoremifene had a statistically significant improvement in all serumlipid parameters to measured.

Example 17 Exemplified SERM Compounds Lowering LDL Cholesterol Levels

Methods:

In addition to Toremifene, other SERM compounds may be similarlyevaluated in clinical trial settings. The following compounds may besimilarly administered as described in Example 1, and their effect inaltering lipid profiles in subjects with prostate cancer, undergoing ADTmay be similarly evaluated. Some of the compounds thus evaluated maycomprise:

Compound (1): N,N-bis(4-hydroxyphenyl)-3,4-dimethylbenzamide;

Compound (2): N,N-bis(4-hydroxyphenyl)-4-propylbenzamide;

Compound (3): 3-fluoro-4-hydroxy-N-(4-hydroxyphenyl)-N-phenylbenzamide;Compound

(4): N,N-bis(4-hydroxyphenyl)-4-pentylbenzamide; and/or Ospemifene.

Example 18

Effects of SERMs on ER-α, ER-β and AR Transactivation

COS or 293 cells were plated in DME without phenol red+10% cs FBS at90,000 cells per well in 24 well plates, and were transfected with 0.25μg of the vector “ERE-LUC”, where a firefly luciferase gene was drivenby two estrogen responsive elements and 0.02 μg of the control CMV-LUC,Renilla where a luciferase gene was driven by a CMV promoter. Also 25 ngof ER-α), 50 ng of ER-β or 12.5 ng of AR were introduced bylipofectamine. All the receptors were cloned from rat tissue into thePCR3.1 vector backbone. Twenty four hours post transfection, cells weretreated with compounds of this invention, estrogen, DHT, and other NRBAsor combinations thereof. Cells were harvested 48 hrs after transfection,and assayed for firefly and Renilla luciferase activity.

Representative examples of the NRBAs of this invention and their %estardiol activity at 100 mM

Compound ER-α ER-β  3a 49.5 61.1  3d 48 37.4  3e 133 32  3l 52.2 46.7 3g 62.5 75.2  3j 62 93.6  3i 77.8 84.2  4a 29.9 32.6  4d 16.8 30.7  4h17.4 29.1  4u 12.8 27.8 10o 12 14 10d 21.4 6.1 10f 85 25 10l 32 13 10w21.9 4.5

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

What is claimed is:
 1. A nuclear receptor binding agent (NRBA) compoundor its isomer, pharmaceutically acceptable salt, ester, or anycombination thereof, represented by the structure of formula VI:

wherein X is CO; R₁ and R₃, are independently halogen, —CHO, —CHNOH,CH═CHCO₂H, hydroxyalkyl group of 1 to 7 carbon atoms, hydroxyl, alkoxygroup of 1 to 7 carbon atoms, cyano, CF₃, NH₂, NHR, NHCOR, sulfonamide,SO₂R, aryl or protected hydroxyl; R₂ is —CHO, —CHNOH, CH═CHCO₂H,hydroxyalkyl, hydroxyl, alkoxy, cyano, CF₃, NH₂, NHR, NHCOR,sulfonamide, SO₂R, aryl, or protected hydroxyl; R₈, R₉, and R₁₀ areindependently hydrogen, halogen, CHO, CHNOH, CH═CHCO₂H, hydroxyalkylgroup of 1 to 7 carbon atoms, hydroxyl, alkoxy group of 1 to 7 carbonatoms, cyano, CF₃, NH₂, NHR, NHCOR, sulfonamide, SO₂R, aryl, orprotected hydroxyl; R is alkyl group of 1 to 7 carbon atoms, hydrogen,haloalkyl group of 1 to 7 carbon atoms, dihaloalkyl group of 1 to 7carbon atoms, trihaloalkyl group of 1 to 7 carbon atoms, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl group of 1 to 7 carbonatoms, CN, NO₂, or OH; and j, k, l are independently 1-4.
 2. The nuclearreceptor binding agent (NRBA) of claim 1 wherein said pharmaceuticallyacceptable salt is an HCl salt.
 3. The nuclear receptor binding agent(NRBA) compound of claim 2 wherein said pharmaceutically acceptable saltis a chloride, phosphate, acetate, oxalate, tartrate, mandelate,citrate, sodium, potassium, ammonium, calcium, ferric hydroxides,isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, orprocaine.
 4. A nuclear receptor binding agent (NRBA) compound of claim1, wherein said compound is:4-hydroxy-N-(4-hydroxyphenyl)-N-(4-fluorophenyl)-benzamide (3m);4-fluoro-3-hydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (10g);3-fluoro-4-hydroxy-N,N-bis(4-hydroxyphenyl)-benzamide (10k); and4-fluoro-N,N-bis(4-hydroxyphenyl)-2-(trifluoromethyl)-benzamide (11x).5. A pharmaceutical composition comprising the nuclear receptor bindingagent (NRBA) compound of claim 1 or its pharmaceutically acceptablesalt, and a suitable carrier or diluent.
 6. A method of binding thenuclear receptor binding agent (NRBA) of claim 1 to an estrogen receptoror an estrogen related receptor, comprising the step of contacting anestrogen receptor with said NRBA.
 7. A method of treating or reducingthe severity of osteoporosis in a subject, the method comprisingadministering a composition comprising the nuclear receptor bindingagent (NRBA) of claim 1 or its pharmaceutically acceptable salt to saidsubject.
 8. A method of treating or reducing the risk of mortality fromcardiovascular disease in a subject, the method comprising administeringa composition comprising the nuclear receptor binding agent (NRBA) ofclaim 1 or its pharmaceutically acceptable salt to said subject.
 9. Amethod of improving a lipid profile in a subject, the method comprisingadministering a pharmaceutical composition comprising the nuclearreceptor binding agent (NRBA) of claim 1 or its pharmaceuticallyacceptable salt to said subject.
 10. A method of reducing the incidenceof, inhibiting, suppressing, or treating androgen-deprivation inducedosteoporosis, bone fractures and/or loss of bone mineral density (BMD)in men having prostate cancer, the method comprising administering apharmaceutical composition comprising the nuclear receptor binding agent(NRBA) of claim 1 or its pharmaceutically acceptable salt, or anycombination thereof to a male subject in need, having prostate cancer.11. A method of ameliorating symptoms and/or clinical complicationsassociated with menopause in a female subject, the method comprisingadministering a pharmaceutical composition comprising the nuclearreceptor binding agent (NRBA) of claim 1 or its pharmaceuticallyacceptable salt to a female menopausal subject.
 12. A method of treatingor reducing the severity of Alzheimer's disease in a subject, the methodcomprising administering a pharmaceutical composition comprising thenuclear receptor binding agent (NRBA) of claim 1 or its pharmaceuticallyacceptable salt to said subject.
 13. A method of treating, suppressing,inhibiting, or reducing the incidence of hot flashes, gynecomastia,and/or hair loss in a male subject having prostate cancer, the methodcomprising administering a pharmaceutical composition comprising thenuclear receptor binding agent (NRBA) of claim 1 or its pharmaceuticallyacceptable salt to said subject.
 14. A method of treating, suppressing,inhibiting or reducing the risk of developing prostate cancer in asubject, the method comprising administering a pharmaceuticalcomposition comprising the nuclear receptor binding agent (NRBA) ofclaim 1 or its pharmaceutically acceptable salt, to said subject.
 15. Amethod of treating, suppressing, inhibiting or reducing the amount ofprecancerous precursors of prostate adenocarcinoma lesions in a subject,the method comprising administering a pharmaceutical compositioncomprising the nuclear receptor binding agent (NRBA) compound of claim 1or its pharmaceutically acceptable salt to said subject.
 16. A method ofclaim 15, wherein said precancerous precursors of prostateadenocarcinoma is prostate intraepithelial neoplasia (PIN).
 17. A methodof treating, preventing, inhibiting or reducing the incidence ofinflammation in a subject, comprising administering a pharmaceuticalcomposition comprising a nuclear receptor binding agent (NRBA) of claim1 or its pharmaceutically acceptable salt to said subject.
 18. A methodof treating, inhibiting or reducing the risk of breast cancer in asubject, comprising administering a pharmaceutical compositioncomprising a nuclear receptor binding agent (NRBA) of claim 1 or itspharmaceutically acceptable salt to said subject.
 19. A method oftreating, inhibiting or reducing the risk of endometrial cancer in asubject, comprising administering a pharmaceutical compositioncomprising a nuclear receptor binding agent (NRBA) of claim 1 or itspharmaceutically acceptable salt to said subject.
 20. A method oftreating, inhibiting or reducing the risk of bladder cancer in asubject, comprising administering a pharmaceutical compositioncomprising a nuclear receptor binding agent (NRBA) compound of claim 1or its pharmaceutically acceptable salt to said subject.
 21. A method oftreating, inhibiting or reducing the risk of colon cancer in a subject,comprising administering a pharmaceutical composition comprising anuclear receptor binding agent (NRBA) of claim 1 or its pharmaceuticallyacceptable salt to said subject.
 22. A method of treating, inhibiting orreducing the risk of leukemia in a subject, comprising administering apharmaceutical composition comprising a nuclear receptor binding agent(NRBA) of claim 1 or its pharmaceutically acceptable salt to saidsubject.
 23. A method of reducing circulating lipid levels in a malesubject with prostate cancer having undergone Androgen DeprivationTherapy (ADT), said method comprising administering to said subject acomposition comprising a nuclear receptor binding agent (NRBA) compoundof claim 1 or its pharmaceutically acceptable salt.
 24. The method ofclaim 23, wherein said lipid levels, which are reduced comprise atriglyceride, low density lipoprotein (LDL) cholesterol, or acombination thereof.
 25. The method of claim 23, wherein said methodcomprises increasing circulating levels of high density lipoprotein(HDL) cholesterol in said subject.
 26. The method of claim 23, whereinsaid method further comprises reducing the ratio of total circulatingcholesterol levels to high density lipoprotein (HDL) levels in saidsubject.
 27. The method of claim 23, wherein said subject furthersuffers from atherosclerosis and its associated diseases, prematureaging, Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis,peripheral vascular insufficiency, renal disease, hyperglycemia, or anycombination thereof.
 28. A method of treating atherosclerosis and itsassociated diseases including cardiovascular disorders, cerebrovasculardisorders, peripheral vascular disorders, and intestinal vasculardisorders in a subject with prostate cancer having undergone AndrogenDeprivation Therapy (ADT), comprising administering to said subject acomposition comprising a nuclear receptor binding agent (NRBA) compoundof claim 1 or its pharmaceutically acceptable salt.
 29. A method oftreating ischemia in a tissue of a subject with prostate cancer havingundergone Androgen Deprivation Therapy (ADT), comprising administeringto said subject a composition comprising a nuclear receptor bindingagent (NRBA) compound of claim 1 or its pharmaceutically acceptablesalt.
 30. A method of treating bone loss in a subject, the methodcomprising administering to said subject a composition comprising anuclear receptor binding agent (NRBA) compound of claim 1 or itspharmaceutically acceptable salt.